A Multi-Center, Randomized, Double-Blind, Sham-Controlled Study to Evaluate the NTX100 Neuromodulation System for Patients With Medication-Refractory Primary Restless Legs Syndrome (RLS) - The RESTFUL Study
Phase: NA
Conditions: Restless Legs Syndrome
Sponsor: Noctrix Health, Inc.

27Nov2023 
 
  
 
A MulƟ-Center, Randomized, Double-Blind, Sham-Controlled Study to 
Evaluate the NTX100 Tonic Motor AcƟvaƟon System for PaƟents with 
MedicaƟon-Refractory Primary Restless Legs Syndrome (RLS) – The 
RESTFUL study 
 
NCT04874155 

Clinical Trial 
Document #: CT-3 (previously CT-04) 
Rev: 2.0 (Superseded Rev A) 
CC#: 660 
Effective: 6/15/2021 
Investigational Plan, Protocol CT-3 
(Pivotal Trial) 
CONFIDENTIAL 
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CLINICAL INVESTIGATIONAL PLAN 
A Multi-Center, Randomized, Double-Blind, Sham-Controlled Study to 
Evaluate the NTX100 Neuromodulation System for Patients with 
Medication-Refractory Primary Restless Legs Syndrome (RLS) – The 
RESTFUL study 
PROTOCOL NUMBER: 
CT-3 (Previously CT-04) 
VERSION:  
2.0 (Superseded Rev A) 
SPONSOR: 
Noctrix Health, Inc.  
5424 Sunol Blvd  
Ste 10-451  
Pleasanton, CA 94566 
804-683-4279
SPONSOR REPRESENTATIVE(S): 
Jonathan Charlesworth, PhD 
Head of Clinical Sciences 
 
 
The information contained in this document is confidential and proprietary property of Noctrix 
Health, Inc. 

 
Clinical Trial 
Document #: CT-3 (previously CT-04) 
Rev: 2.0 (Superseded Rev A) 
CC#: 660 
Effective: 6/15/2021 
Investigational Plan, Protocol CT-3 
(Pivotal Trial) 
 
CONFIDENTIAL 
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Investigator Study Acknowledgement 
 
Read and initial below. 
 
____ 
I understand this protocol contains information that is confidential and proprietary to 
Noctrix Health, Inc. 
____ 
Any additional information added to this protocol is also confidential and proprietary to 
Noctrix Health, Inc. and must be treated in the same manner as the contents of this 
protocol. 
____ 
I have read the entire protocol. 
____ 
I understand what the protocol asks me to do as an Investigator. 
____ 
I will conduct this study following this protocol and will make a reasonable effort to 
complete the study in the time noted. 
____ 
I will provide this protocol to study staff under my direct supervision. My study staff will 
keep the protocol and associated documents confidential.  
____ 
I will discuss this information with the study staff to ensure they are fully informed about 
the study and the test articles.  
____ 
I will not start enrolling in this study until it is approved by a governing Institutional Review 
Board.  
____ 
I understand the study may be terminated or enrollment suspended at any time by Noctrix 
Health, Inc., with or without cause, or by me if it becomes necessary to protect the interests 
of the study subjects. 
 
 
____________________________________ 
Name of Investigator 
 
____________________________________ 
_____________________ 
Investigator Signature 
 
 
 
 
Date 
 
 
 

 
Clinical Trial 
Document #: CT-3 (previously CT-04) 
Rev: 2.0 (Superseded Rev A) 
CC#: 660 
Effective: 6/15/2021 
Investigational Plan, Protocol CT-3 
(Pivotal Trial) 
 
CONFIDENTIAL 
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Page 3 of 45 
 
 
Table of Contents 
Investigator Study Acknowledgement ......................................................................................................... 2 
Study Design Overview Synopsis .................................................................................................................. 5 
Abbreviations ............................................................................................................................................... 7 
1. 
Background .......................................................................................................................................... 7 
2. 
Regulatory Status ............................................................................................................................... 11 
3. 
Objective ............................................................................................................................................ 11 
4. 
Study Design ....................................................................................................................................... 11 
5. 
Blinding ............................................................................................................................................... 12 
6. 
Duration ............................................................................................................................................. 13 
7. 
Study population overview ................................................................................................................ 13 
7.1. 
Inclusion criteria (IC) .................................................................................................................. 13 
7.2. 
Exclusion criteria (EC) ................................................................................................................. 14 
7.3. 
Definition of RLS Refractory to Medication (IC #2) .................................................................... 16 
8. 
Investigational Device ........................................................................................................................ 17 
10. 
Adverse Events ............................................................................................................................... 20 
11. 
Device Tracking .............................................................................................................................. 24 
12. 
Device Deficiencies and Malfunctions ............................................................................................ 24 
13. 
Ethical and Regulatory Considerations ........................................................................................... 24 
13.1. 
Compliance with Good Clinical Research Practice ..................................................................... 24 
13.4. 
Protocol Compliance .................................................................................................................. 26 
13.6. 
Study Monitoring ....................................................................................................................... 26 
13.7. 
Safety Reporting ......................................................................................................................... 28 
13.8. 
Electronic Case Report Forms/Electronic Data Capture ............................................................. 29 
13.9. 
Quality Assurance Audits ............................................................................................................ 30 
13.10. 
Records Retention .................................................................................................................. 30 
13.11. 
Publication and Reporting of Study Results ........................................................................... 30 
14. 
Personnel Responsibilities .............................................................................................................. 31 
14.1. 
Investigator responsibilities: ...................................................................................................... 31 

 
Clinical Trial 
Document #: CT-3 (previously CT-04) 
Rev: 2.0 (Superseded Rev A) 
CC#: 660 
Effective: 6/15/2021 
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14.2. 
Sponsor Responsibilities ............................................................................................................. 32 
15. 
Investigator Qualifications ............................................................................................................. 32 
16. 
Study Procedures ........................................................................................................................... 32 
17. 
Study Endpoints ............................................................................................................................. 40 
 
 
 

 
Clinical Trial 
Document #: CT-3 (previously CT-04) 
Rev: 2.0 (Superseded Rev A) 
CC#: 660 
Effective: 6/15/2021 
Investigational Plan, Protocol CT-3 
(Pivotal Trial) 
 
CONFIDENTIAL 
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Study Design Overview Synopsis 
Title  
A Multi-Center, Randomized, Double-Blind, Sham-Controlled Study to Evaluate the NTX100 
Neuromodulation System for Patients with Medication-Refractory Primary Restless Legs 
Syndrome (RLS) – The RESTFUL Study 
Study Device 
NTX100 Neuromodulation System (“NTX100”), an investigational device developed by 
Noctrix Health, Inc.  NTX100 is an external (non-implantable) neurostimulation device that is 
worn bilaterally on the lower legs. 
Study Objective 
To provide comparative evidence assessing clinically meaningful benefit in the treatment of 
patients with moderate to severe medication-refractory primary RLS with the NTX100 
Neuromodulation System.   
Study Population 
Adults with moderate to severe medication-refractory primary RLS. 
Study Duration 
The treatment period is 8 weeks (56-days) 
Study Interventions 
• 
Active: NTX100 programmed to ACTIVE mode 
• 
Sham: NTX100 programmed to SHAM mode 
For each, subjects are instructed to self-administer stimulation on each night that RLS 
symptoms are present, as needed, to reduce and relieve RLS symptoms.  Multiple stimulation 
sessions may be applied with a maximum of 120 total minutes of stimulation per night. 
Subjects who have been prescribed an FDA-approved drug(s) to treat RLS symptoms will be 
instructed to maintain a constant dose and schedule of this drug(s) throughout the study. 
Study Design  
The 8 week follow-up duration will consist of two phases: 
Phase 1: Randomized Double-Blind Phase lasting 4-wks, during which subjects will be 
randomized 1:1 into Active or Sham study arms  
Phase 2: Open-Label Phase lasting 4-wks, during which all subjects will receive open-label 
Active treatment  
 

 
Clinical Trial 
Document #: CT-3 (previously CT-04) 
Rev: 2.0 (Superseded Rev A) 
CC#: 660 
Effective: 6/15/2021 
Investigational Plan, Protocol CT-3 
(Pivotal Trial) 
 
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Maximum Study 
Duration 
The study is estimated to be completed 18 months after the study opens to enrollment. 
Planned enrollment: 
Approximately 132 subjects will be randomized (66 per Phase 1 study arm).  Subjects who 
meet eligibility criteria will be randomized (1:1) to Active and Sham arms for Phase 1; 
randomization will be stratified by site at an allocation of 1:1 for the Active and Sham arms.  
Number of Clinical 
Sites 
4 to 8 clinical sites within the United States.   
Primary Efficacy 
Endpoint 
The primary outcome measure will be responder rate on the CGI-I scale at Week 4 of Phase 1 
relative to Baseline and compared between the study arms.   
 
Responder rate for the 7-point CGI-I scale will be defined as the proportion of responses of 
“Much Improved” or “Very Much Improved”.   
Key Secondary 
Efficacy Endpoints 
For all subjects: 
1. PGI-I responder rate (defined as for CGI-I) at Week 4 of Phase 1, relative to baseline 
and compared between study arms. 
2. Mean reduction in IRLS score at Week 4 of Phase 1, relative to Baseline and 
compared between study arms. 
3. Mean reduction in MOS-II score at Week 4 of Phase 1, relative to Baseline and 
compared between study arms. 
4. Mean reduction in MOS-I score at Week 4 of Phase 1, relative to Baseline and 
compared between study arms. 
Safety Endpoint 
Descriptive analysis of adverse events for both study arms, classified and tabulated by 
seriousness, relationship to the device, and severity. 
Additional Study 
Assessments  
• 
Daily Questionnaire  
• 
Subject characterization 
• 
Refractory categorization 
• 
Medical history 
• 
Concomitant medications 
• 
Weekly questionnaire 
• 
Custom RLS questionnaire 
• 
Blinding assessment 
 
 

 
Clinical Trial 
Document #: CT-3 (previously CT-04) 
Rev: 2.0 (Superseded Rev A) 
CC#: 660 
Effective: 6/15/2021 
Investigational Plan, Protocol CT-3 
(Pivotal Trial) 
 
CONFIDENTIAL 
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Abbreviations 
AE 
Adverse Event 
AO 
Anticipated Observation 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impressions – Improvement 
CRF 
Case Report Form 
DCF 
EDC 
FDA 
Data Clarification Form 
Electronic Data Capture 
Food and Drug Administration 
GCP 
Good Clinical Practice 
IRB 
IRLS 
Institutional Review Board 
International Restless Legs Syndrome Study Group Rating Scale 
IRLSS 
International Restless Legs Syndrome Society 
ISO 
MOS 
NPNS 
International Organization for Standardization 
Medical Outcomes Study 
Non-invasive peripheral nerve stimulation 
NSR 
PGI-I 
Non-Significant Risk 
Patient Global Impressions – Improvement 
QA 
Quality Assurance 
RLS 
 
Restless Legs Syndrome 
SAE 
Serious Adverse Event 
TENS 
Transcutaneous Electrical Nerve Stimulation 
USADE 
Unanticipated Serious Adverse Device Effect 
 
 
 
 
1. Background 
A clinical need has been identified of improved treatment for those suffering with primary idiopathic 
restless legs syndrome (RLS). Patients with RLS have a strong urge with sensations of tingling/pain, 
usually in their legs, and often present with a primary complaint of not being able to fall asleep 

 
Clinical Trial 
Document #: CT-3 (previously CT-04) 
Rev: 2.0 (Superseded Rev A) 
CC#: 660 
Effective: 6/15/2021 
Investigational Plan, Protocol CT-3 
(Pivotal Trial) 
 
CONFIDENTIAL 
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Page 8 of 45 
 
regularly.  This leads to significant quality of life degradation, depression, daytime sleepiness, lack of 
productivity and a host of downstream effects associated with lack of quality sleep. 
1.1. Restless leg syndrome: Background 
Restless legs syndrome (RLS) is a sensorimotor disorder that is characterized by a distressing urge to 
move the legs and in some cases, other parts of the body such as arms [1].  The diagnosis is made by 
a response to five hallmark identifying criteria instituted by the International Restless Legs Syndrome 
Society (IRLSS) [2], as quoted below: 
“1. An urge to move the legs usually but not always accompanied by or felt to be caused by 
uncomfortable and unpleasant sensations in the legs. 
2. The urge to move the legs and any accompanying unpleasant sensations begin or worsen during 
periods of rest or inactivity such as lying down or sitting. 
3. The urge to move the legs and any accompanying unpleasant sensations are partially or totally relieved 
by movement, such as walking or stretching, at least as long as the activity continues.  
4. The urge to move the legs and any accompanying unpleasant sensations during rest or inactivity only 
occur or are worse in the evening or night than during the day. 
5. The occurrence of the above features are not solely accounted for as symptoms primary to another 
medical or a behavioral condition (e.g., myalgia, venous stasis, leg edema, arthritis, leg cramps, positional 
discomfort, habitual foot tapping).” 
Diagnostically, RLS is considered either primary, often occurring within families, or secondary, 
developing in association with other conditions (such as iron deficiency anemia, pregnancy or end-
stage renal disease). 
1.2. Epidemiology 
In the United States, RLS is believed to affect more than 10 million adults and an estimated 1.5 million 
children and adolescents [3].  About one-third of those with RLS symptoms are bothered sufficiently 
enough to seek medical attention. Epidemiologic studies also show that women are at least 50% more 
susceptible to RLS than men and RLS is more common in older adults, although it can occur in some 
as early as the pre-school years.  
1.3. Clinical treatments available 

 
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The current standard of care involves initial prescription of dopaminergic medications – such as 
Requip, Mirapex, and Neupro – which initially provide symptomatic relief but often become 
ineffective over continued usage [4].  Tolerance to these medications is rapid and well-documented 
[5]; approximately 10% of patients per year become refractory to these medications, and fewer than 
20% patients have sustained benefits lasting 10 years or longer [6]. It is also now understood that 
dopaminergic medications cause what is known as “augmentation”, or paradoxical progressive 
worsening of RLS symptoms that is much faster than the natural progression of the condition.  Due to 
augmentation, patients on dopaminergic medications require increasingly higher doses [7]. Maximal 
dosage is limited by an increasing risk of side-effects at higher doses, which include compulsive 
behaviors including substance abuse, hypersexuality, and gambling [8].  As a result of these downsides 
of dopaminergic agents, a minority of clinicians are starting to prescribe gabapentinioids (e.g. 
Horizant) as an alternative first-line of treatment; these medications do not typically lead to 
augmentation but confer risks such as respiratory depression [9], dizziness, and somnolence during 
the day. 
For the large subpopulation of patients who become refractory to dopaminergic medications – 
typically due to augmentation – there are no FDA approved treatment options and no safe treatment 
options.  As a result of tolerance, augmentation, and dosage limitations, RLS patients often continue 
to suffer from moderate-severe RLS symptoms while continuing to be reliant on high doses of 
dopaminergic medications to provide a small degree of relief.  To address the massive unmet need, 
the leading clinicians involved with RLS advocate prescribing off-label opioids [10].  The leading 
options – oxycodone and methadone, have well documented risks, which include addiction, 
dependence, overdose, and occasionally death.  This situation is especially concerning because 
primary RLS typically starts in middle age or earlier and persists throughout life, thus patients may end 
up reliant on opioids for the final decades of their lives.   
 
1.4. Investigational Procedure 
The investigational device – the NTX100 Neuromodulation System – is a non-invasive nerve peripheral 
stimulation (NPNS) device developed by Noctrix Health, Inc. (Sponsor) and designed to bilaterally 

 
Clinical Trial 
Document #: CT-3 (previously CT-04) 
Rev: 2.0 (Superseded Rev A) 
CC#: 660 
Effective: 6/15/2021 
Investigational Plan, Protocol CT-3 
(Pivotal Trial) 
 
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stimulate the common peroneal nerve. Stimulation electrodes are positioned superficially and 
bilaterally on the lower legs over the head of the fibula bone, a position where the peroneal nerve is 
closest to the skin.  This nerve target innervates regions of the lower extremities commonly associated 
with RLS symptoms.  
1.5 Rationale 
The NTX100 Neuromodulation System is a NPNS device that is inspired by the temporary symptomatic 
relief that RLS patients experience during voluntary movement of their lower extremities.  One of the 
fundamental diagnostic criteria for RLS is the fact that patients report short-lived symptomatic relief 
during voluntary movement of their legs and feet [2].  This is conceptually similar to the gate-control 
theory mechanism of pain relief, wherein activation of large sensory fibers suppresses pain signals.  
However, for RLS, it appears that muscle activation is especially effective – activating sensory fibers 
of the affected region of the body (e.g. via rubbing or touching) does not typically result in similar 
relief.  
Non-invasive electrical stimulation is known to elicit muscle activation – this feature is used by two 
types of approved medical devices – powered muscle stimulators (21 CFR 890.5850) and external 
functional neuromuscular stimulators (21 CFR 882.5810).  However, these devices tend to have 
distracting side-effects including paresthesia and phasic muscle twitches, and thus are incompatible 
with sleep and inappropriate for use in treating a sleep condition such as RLS.  In contrast, the NPNS 
investigational device tested here produces waveforms that are designed to generate muscle 
activation without these paresthesia and phasic muscle twitches.  Therefore, this technology may be 
compatible with sleep. 
The NTX100 Neuromodulation System stimulates the peroneal nerve at its most superficial position 
over to the head of the fibula bone to activate muscles of the lower leg including the tibialis anterior 
at intensity levels that are comfortable and non-distracting.  Such comfortable tonic muscle activation 
is designed to suppress RLS symptoms in a manner similar to voluntary movement – but unlike 
voluntary movement, may be compatible with sleep.  Moreover, the output waveforms and intensities 
of the NTX100 Neuromodulation System are similar to Functional Electrical Neuromuscular 
Stimulators and Transcutaneous Electric Nerve Stimulation (TENS) Devices for treatment of pain, two 

 
Clinical Trial 
Document #: CT-3 (previously CT-04) 
Rev: 2.0 (Superseded Rev A) 
CC#: 660 
Effective: 6/15/2021 
Investigational Plan, Protocol CT-3 
(Pivotal Trial) 
 
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Page 11 of 45 
 
classes of devices designated nonsignificant risk per 21 CFR 812.3.  Therefore, there is a reasonable 
expectation that the NTX100 Neuromodulation System will lack significant risks. 
This study evaluates the effects of NPNS on the symptoms of RLS during in-home subject-administered 
stimulation.  This approach is useful for evaluating safety, usability, tolerability, and preliminary 
efficacy in a realistic environment - thus identifying any and all barriers to effective and tolerable use. 
2. Regulatory Status 
The Sponsor has determined that the investigational device in this study – the NTX100 
Neuromodulation System – is a nonsignificant risk device under 21 CFR §812.2(b).  In previously 
approved investigational protocols RLS-SNS01 and CT-03, Western IRB confirmed that earlier NTX100 
Neuromodulation System prototypes - with comparable stimulation output - were nonsignificant risk 
devices. Therefore, an approved Investigational Device Exemption (IDE) from FDA is not required to 
legally perform the study described herein in the US.  
The rationale for the nonsignificant risk determination is that the NTX100 Neuromodulation System 
has equivalent risks and comparable electrical stimulation parameters to Transcutaneous Electric 
Nerve Stimulation (TENS) Devices for treatment of pain (except for chest pain/angina),” which are 
Nonsignificant risk (NSR) device per the FDA guidance on Significant Risk and Nonsignificant Risk 
Medical Device Studies [11]. 
3. Objective 
The study objective is to provide comparative evidence assessing clinically meaningful benefit in the 
treatment of patients with moderate to severe medication-refractory RLS with the NTX100 
Neuromodulation System.   
4. Study Design 
The study consists of a 4-wk prospective, randomized, sham-controlled, double-blinded phase (Phase 
1) followed by a 4-wk prospective open-label phase (Phase 2) for a total of 8-wks of follow-up per 
subject.  The design of the trial is illustrated in the flowchart below (Figure 1).   

 
Clinical Trial 
Document #: CT-3 (previously CT-04) 
Rev: 2.0 (Superseded Rev A) 
CC#: 660 
Effective: 6/15/2021 
Investigational Plan, Protocol CT-3 
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Phase 1 (4-wks): Subjects who pass screening will be randomly allocated at a 1:1 ratio to receive Active 
or Sham treatment throughout the 4-wk duration of Phase 1.  The primary and key secondary efficacy 
endpoints of the study will compare the final week of Phase 1 to study entry (“Baseline”). 
Phase 2 (4-wks): All subjects who complete Phase 1 will be allocated to receive open-label Active 
treatment throughout the 4-wk duration of Phase 2.  Instructions for device use will remain the same 
as during Phase 1. 
 
Figure 1: Study Design Flowchart 
 
 
5. Blinding 
Phase 1 will be double-blind. Information about treatment assignment will be concealed from subjects, 
investigators, and site staff, except as required in cases of safety emergencies.  In additional, all sponsor 
staff interacting directly with the research staff or investigators (e.g. in a monitoring capacity) or subjects 
(e.g. in a device specialist capacity) will be blinded to the Phase 1 treatment assignment throughout the 
study (even during Phase 2).   
Phase 2 will be open-label.  At the beginning of Phase 2, the treatment assignment on each device will be 
set to Active for all subjects.  This will take place without revealing the previous treatment assignment 
during Phase 1.   
Active and sham devices will be physically identical and will provide identical visual feedback during 
operation.  Both active and sham mode will have an initial ramp-up in stimulation intensity lasting 

 
Clinical Trial 
Document #: CT-3 (previously CT-04) 
Rev: 2.0 (Superseded Rev A) 
CC#: 660 
Effective: 6/15/2021 
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approximately 30 seconds and during which sensations are typically noticeable.  No subjects with prior 
neurostimulation experience with NTX100 or any other neurostimulation devices will be enrolled.   
The investigator must contact the sponsor if the need to unbreak blinding arises or within 24 hours of an 
actual unblinding. The Investigator should not open the unblinding envelop UNLESS knowledge of the 
subject’s treatment assignment is required for the subject’s clinical care and safety. Documentation of 
breaking the blind should be recorded in the subjects Narrative eCRF with the date and time the blind 
was broken, and the names of the personnel involved.  
6. Duration 
The study will be completed approximately 18 months after the study opens to accrual or after 132 
subjects have been enrolled, whichever occurs first. 
7. Study population overview 
The study population will consist of adults with moderate-severe primary RLS.  The following inclusion 
and exclusion criteria are designed to reduce confounding variables and reduce risk.   
7.1. Inclusion criteria (IC) 
All subjects are required to meet the following inclusion criteria in order to be considered eligible for 
participation in this study: 
1. Subject has received a medical diagnosis of primary restless legs syndrome (RLS).  
2. Subject is refractory to RLS medication (as defined in section 7.3). 
3. Subject has moderate-severe RLS symptoms as defined by a score of 15 or greater points on IRLS 
(International Restless Legs Syndrome Study Group Rating Scale [12]) over the week prior to study 
entry. 
4. Subject has RLS symptoms 2 or more nights per week during the week prior to study entry as 
defined by a score of 2, 3, or 4 on IRLS question #7. 
5. RLS symptoms are most significant in the subject’s lower legs and/or feet. 
6. RLS symptoms are most significant at bedtime, after bedtime, and/or in the 2 hours before 
bedtime. 

 
Clinical Trial 
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CC#: 660 
Effective: 6/15/2021 
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7. RLS symptoms between 10am and 6pm are not severe. 
8. Subject agrees to not change dosage or schedule of any medications that are known to impact RLS 
symptoms during the study, including RLS medications, antidepressants, sleep medications, or 
sedative antihistamines. 
9. Subject agrees to not make major lifestyle changes during the study that would significantly affect 
bedtime, such as major changes to diet, exercise, or career. 
10. Subject possesses the necessary equipment, internet/phone accessibility, and communication 
ability to complete electronic questionnaires and respond to electronic communications and 
phone calls from the research staff throughout the in-home portion of the study. 
11. Subject is ≥ 22 and ≤ 79 years of age when written informed consent is obtained. 
12. Subject has signed a valid, IRB-approved informed consent form, can understand the requirements 
of the study and instructions for device usage, and can converse in English 
7.2. Exclusion criteria (EC) 
Subjects will be excluded from participating in this study if they meet any of the following exclusion 
criteria: 
1. Subject has RLS that is known to be caused by another diagnosed condition (i.e. secondary RLS). 
2. Subject is taking an unstable or inconsistent dose or schedule of medication that is likely to impact 
RLS symptoms, such as antidepressants, sleep medications, or sedative antihistamines or has 
changed dosage within the past 30 days. 
3. Subject has changed dose and schedule of RLS medications within the month prior to study entry 
or is otherwise on an inconsistent dose or schedule of RLS medications. 
4. Subject has prior experience with neurostimulation devices developed by the study sponsor, has 
prior experience using neurostimulation devices to treat RLS symptoms, or intends to use a 
neurostimulation device other than the study device during the study period. 
5. Subject was misdiagnosed with RLS, as determined by the investigator (e.g. actual diagnosis of 
PLMD, arthritis, leg spasms or neuropathy without comorbid RLS). 
6. Subject has a primary sleep disorder other than RLS that significantly interferes with sleep at the 
present time (e.g. obstructive sleep apnea stably controlled via CPAP would not be an exclusion).   

 
Clinical Trial 
Document #: CT-3 (previously CT-04) 
Rev: 2.0 (Superseded Rev A) 
CC#: 660 
Effective: 6/15/2021 
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(Pivotal Trial) 
 
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7. Subject has active medical device implant anywhere in the body (including but not limited to 
pacemakers, spinal cord stimulators, deep brain stimulators) or metal implant at the site of study 
device electrode application. 
8. Subject has severe peripheral neuropathy affecting the lower legs and/or subject has neuropathy 
and is unable to clearly distinguish between symptoms of neuropathy and symptoms of RLS. 
9. Subject reports that bedtime is typically outside of 9pm-3am or reports that bedtime regularly 
varies by more than 4 hours, such as due to shift work. 
10. On nights with no RLS symptoms (if any), subject reports typical sleep onset latency of >60min. 
11. Subject has been diagnosed with one of the following conditions:  
• Epilepsy or other seizure disorder  
• Current, active or acute or chronic infection other than common cold 
• A malignancy within the past 5 years (not including basal or squamous cell skin cancer) 
• Stage 4-5 chronic kidney disease or renal failure 
• Severe movement disorder symptoms (Parkinson’s disease, Huntington’s disease, dyskinesia, 
dystonia) 
• Deep vein thrombosis 
• Multiple sclerosis 
12. Subject has moderate or severe cognitive disorder or mental illness. 
13. Subject has current diagnosis of iron-deficient anemia or history of iron-deficient anemia within 
the past year. 
14. Subject has known allergy to device materials, electrode gel, polyurethane foam, or lycra (or 
severe previous reaction to medical adhesives or bandages). 
15. Subject has severe edema affecting lower legs. 
16. Subject has any of the following at or near the location of device application. 
• Acute injury 
• Cellulitis 
• Open sores 

 
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• Other skin condition 
17. Subject is on dialysis or anticipated to start dialysis while participating in the study. 
18. During the NTX100 calibration process, which is identical for subjects in the active and sham arms, 
subject reports not feeling stimulation sensations up to an intensity of 30mA, the subject finds 
stimulation intensities less than 15 mA to be uncomfortable or distracting, or the device does not 
properly fit the subject. 
19. Subject has received another investigational device or drug within 30 days before study entry, is 
planning to receive another investigational device or drug during the study, or is planning to 
change RLS medications during the study.  
20. Subject has undergone a major surgery (excluding dental work) in the 30 days prior to study entry. 
21. Subject is unable or unwilling to comply with study requirements. 
22. Subject is pregnant or trying to become pregnant. 
23. Subject has a medical condition not listed above that may affect validity of the study as 
determined by the investigator. 
24. Subject has a medical condition not listed above that may put the subject at risk as determined by 
the investigator. 
7.3. Definition of RLS Refractory to Medication (IC #2) 
For inclusion criterion #2, the following definition of refractory will be used: 
The patient has failed at least one prescription medication administered to treat RLS* for one or more 
of the following reasons, as determined by the investigator:  
1. Adverse effects associated with the medication are intolerable.  
2. Patient exhibits symptoms of augmentation. 
3. Efficacy has reduced to the point where an up titration would be needed to maintain a 
sufficient response to medication.  
4. The patient lacks sufficient response to medication at the maximum approved or 
recommended dosage.**  

 
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5. The patient lacks sufficient response to medication at the maximum tolerable dosage due 
to adverse effects.  
*Failure of any of the following prescription medications is sufficient to demonstrate that a patient is 
refractory: Ropinirole (FDA-approved), Pramipexole (FDA-approved), Rotigotine (FDA-approved), 
Gabapentin enacarbil (FDA-approved), Pregabalin (not FDA-approved for RLS, but administered in 
clinical practice), Gabapentin (not FDA-approved for RLS, but administered in clinical practice).  
** per FDA-approved dosage regimen or per RLS consensus statement in the case of off-label 
medications (Pregabalin or Gabapentin). 
8. Investigational Device 
8.1.  Description 
The NTX100 Neuromodulation System is positioned and worn bilaterally on the legs with stimulation 
electrodes over the head of the fibula bone, thus targeting the common peroneal nerve – this nerve 
target innervates regions of the lower extremities commonly associated with RLS symptoms. 
For each leg, the NTX100 Neuromodulation System consists of (1) one stimulation unit, (2) two or 
more electrode areas, and (3) a mechanism for attachment to leg, described below. 
• The (1) stimulation unit will: 
o be battery-powered and contain a rechargeable battery and connector for recharging,  
o contain a circuit board that generates the stimulation waveform, 
o contain controls that the subject can use to activate stimulation, 
o contain controls that the subject can use to adjust the intensity of stimulation within a 
range programmed by the researcher, 
o contain an electronic connection mechanism to deliver a stimulation waveform to the 
electrodes, 
o contain an interface that the researcher can use to program the range of stimulation 
intensities, program the mode of stimulation (active or sham), and download data on 
compliance and functionality.  
• The (2) electrodes areas will each: 

 
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o be an electrolyte-containing medium or a hydrogel material, 
o be disposable, allowing for at least 1 night of use by one subject, 
o be attached to the stimulation device by using snaps, magnetic connectors, conductive 
adhesives, shielded or insulated wires, hook and loop fasteners, or similarly secure 
connectors, 
o have an electrode surface area between 5cm2 and 50cm2. 
• The (3) attachment mechanism will: 
o secure the device containing the disposable electrode areas to the body via straps and/or 
additional biocompatible adhesives. 
 
Description of stimulation parameter ranges allowed by protocol: 
• 
Pulse amplitude: up to 45mA 
• 
Frequency: 2kHz - 6kHz  
• 
Pulse width: 80 - 250 microseconds (depending on frequency) 
• 
Duty cycle: 25-100% 
• 
Pulse shape: Charge-balanced 
• 
Duration: up to 60 minutes per session (up to 120 minutes per day) 
 
8.2.  Instructions for Use and Administration 
Use of the NTX100 Investigational device is described briefly herein. For details see Instructions 
for Use. 
8.2.1. Route of administration 
The NTX100 Neuromodulation System is designed to stimulate the common peroneal nerve; 
stimulation electrodes within the device are positioned superficially and bilaterally on the lower 
legs over the head of the fibula bone, a position where the peroneal nerve is close to the skin.  This 
nerve target innervates regions of the lower extremities commonly associated with RLS 
symptoms. 
8.2.2. Dosage and dosage regimen 

 
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The dosage regimen depends on the intensity, timing, and duration of stimulation: 
1. Intensity.  The setpoint stimulation intensity may be the lesser of (a) the maximal intensity that 
the subject reports is non-distracting and comfortable, as determined in the calibration session 
described in the instructions for device use and (b) the maximal intensity for each set of 
stimulation parameters, as determined based on device output capabilities.  Subjects may be 
allowed to adjust stimulation intensity from the setpoint stimulation intensity, but only within a 
limited pre-programmed range.  For example, the subject may increase intensity if symptoms are 
severe or reduce intensity if symptoms are mild. 
2. Timing. Subjects may be instructed to administer stimulation primarily after RLS symptoms 
become noticeable and before the RLS symptoms become severe. 
3. Duration. Each session of stimulation may last 30 minutes.  Stimulation may be activated for up 
to 120 minutes per day (e.g., up to 4 x 30-minute sessions), depending on the timing, duration, 
and severity of RLS symptoms for the specific subject.   
8.3.  Contraindications 
The following are contraindications to device usage: 
• Diagnosis of epilepsy or other seizure disorder,  
• Active medical device implant anywhere in the body, including but not limited to 
pacemakers, spinal cord stimulators, deep brain stimulators 
• Metal implant at the site of study device application 
• Known allergy to device materials (or severe previous reaction to medical adhesives or 
bandages) 
• Cellulitis, open sores, or acute injury at or near the location of device electrode application 
9. Risks 
9.1. Investigational device risks 
NPNS devices such as NTX100 Neuromodulation System result in a known potential for the following 
anticipated observations, which are typically mild to moderate, transient in nature, and resolve over 
time. 

 
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o Mild skin irritation from use of adhesive electrodes and/or secondary attachment 
mechanism. 
o Discomfort, paresthesia, or otherwise irritating or uncomfortable sensations during 
active electrical stimulation.   
§ This risk is reduced by calibrating the stimulation intensity. 
o Temporary interference with sleep while wearing the device: 
§ For some individuals, device may be uncomfortable, thus interfering with sleep 
while wearing the device. 
§ For some individuals, this device may interfere with preferred sleep positions, 
thus interfering with sleep during usage. 
o Temporary increase in RLS symptoms while wearing the device: 
§ For some individuals, this device may interfere with voluntary leg movements 
used to relieve RLS symptoms, thus leading to a temporary increase in RLS 
symptoms. 
§ In some cases, this device may otherwise lead to a temporary increase in RLS 
symptoms during active stimulation for other reasons. 
• This risk may be reduced by calibrating the stimulation intensity and/or 
adjusting the schedule of stimulation. 
10. Adverse Events 
Anticipated observations (e.g. common treatment effects) and adverse events occurring during the 
study will be recorded. Descriptions of anticipated observations and AEs will include the date of onset, 
the date it ended, the severity, the relationship to study device, and the outcome.  All reported AEs 
will be summarized by the number of subjects reporting AEs, system organ class (where applicable), 
severity, seriousness, and relationship to study device.  
The study Investigator and Coordinator will evaluate, characterize and record in the electronic Case 
Report Form (eCRF) all adverse events (AEs) occurring in all subjects from the time of enrollment to 
study exit (or premature withdrawal).  Adverse events unresolved at study exit will be followed by the 

 
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Investigator until resolution occurs or at least 60 days after the subject’s participation in the study is 
complete. AEs may be reported spontaneously by the subject or detected by the Investigator or 
Coordinator.  AEs should be evaluated for diagnoses not just symptoms (i.e., “angina”, not “chest 
pain”). 
In addition to verbatim terms, the Sponsor may categorize all AEs using MedDRA preferred terms (PT) 
and system organ classes (SOC).  Analysis may report both verbatim and MedDRA terms. 
10.1. Adverse Event Definitions 
An adverse event (AE) is any untoward medical occurrence, independent of its association with the 
investigational device.  AEs also include any adverse laboratory signs or physical exam findings.   
A serious adverse event (SAE1) is any AE that: 
• led to a death, 
• led to a serious deterioration in the health of the subject that: 
• resulted in a life-threatening illness or injury, 
• resulted in a permanent impairment of a body structure or a body function, 
• required in-patient hospitalization or prolongation of existing hospitalization, 
• resulted in medical or surgical intervention to prevent permanent impairment to body 
structure or a body function 
• or led to fetal distress, fetal death or a congenital abnormality or birth defect. 
A device-related SAE is an event meeting the SAE definition above that is also rated as probably or 
definitely related the investigational device. No device-related SAEs have been reported in prior 
studies. Note that an elective or pre-planned hospitalization for a condition that did not worsen during 
the study is not an AE. 
An unanticipated serious adverse device effect (USADE) is any SAE that is caused by, or associated 
with, a device, if that effect, problem, or death was not previously identified in nature, severity, or 
degree of incidence in the investigational plan or application (including a supplementary plan or 
application). 
 
1 Definition from ISO14155:2011 

 
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10.2. AE Severity and Relatedness 
Each AE occurring in the study will be characterized by the study Investigator as to severity (Table 1) 
and relatedness (Table 2). 
 
Table 1.  AE Severity Grading System. 
Grade 
Brief description 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2 
Moderate; minimal, local, or non-invasive intervention indicated; limiting age-
appropriate instrumental ADLa 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADLb 
Grade 4 
Life-threatening consequences; urgent intervention indicated 
Grade 5 
Death related to adverse event 
a'Instrumental ADL' refers to activities of daily living such as preparing meals, shopping for groceries 
or clothes, using the telephone, and managing money. b'Self-care ADL' refers to bathing, dressing 
and undressing, feeding oneself, using the toilet, taking medications, and not being bedridden. From 
the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 NCI, NIH, DHHS. 
May 29, 2009 NIH publication #- 09-7473. 
 
Table 2. AE Relatedness Grading System.* 
Grade 
Relationship of 
AE to study 
device 
Description 
5 
Definite 
An event that follows a reasonable temporal sequence from 
administration of the study device; that follows a known or 
expected response pattern to the study device; and that is 
confirmed by improvement on stopping. 

 
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4 
Probable 
An event that follows a reasonable temporal sequence from 
administration of the study device; that follows a known or 
expected response pattern to the study device; and that is 
unlikely to have been caused by concurrent/underlying illness 
or other drugs, procedures, or other causes. 
3 
Possible 
An event that follows a reasonable temporal sequence from 
administration of the study device; that follows a known or 
expected response pattern to the study device; but may have 
been caused by concurrent/underlying illness, drugs, procedure, 
or other causes. 
2 
Unlikely 
An event that does not follow a reasonable temporal sequence 
from administration of the study device; that does not follow a 
known or expected response pattern to the study device, or 
most likely was caused by concurrent/underlying illness, drugs, 
procedure, or other causes, because of their known effects. 
1 
Not related 
An event almost certainly caused by concurrent/underlying 
illness, drugs, procedure, or other causes. 
* AEs occurring before treatment with the study device will be categorized as unrelated to the study 
device. 
10.3. Adverse Event Reporting 
Investigators must report all SAEs to the study Sponsor and governing IRB within 3 business days or 
according to local IRB guidelines.  Investigators should call the study sponsor immediately upon 
becoming aware of the occurrence of an SAE.  The sponsor will contact the independent medical 
reviewer, to assist in assessing any safety concerns, if needed. The Investigator should be able and 
willing to provide further information on the specific event when requested by the study Sponsor.  If 
the Investigator learns of an SAE that occurs within 1 month after the subject completes the study, 
he/she should notify the Sponsor.  Investigators must also report all AEs to the governing IRB as 
determined by that IRB. 
Prompt AE evaluation: 
• protects the safety of study subjects;  
• aids in understanding the overall safety profile of the device;  
• prompts, if necessary, modification to the study protocol 

 
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• allows improvements in study design or procedures; and  
• adheres with standard good clinical practices. 
11.  Device Tracking 
The Sponsor will send the investigational devices to the Investigator. The Investigator must house 
study devices in a secure location.   
The Investigator must carefully and completely track receipt, use and disposition of all investigational 
devices. The Sponsor will track sending and receiving of devices.  The Sponsor will monitor site device 
accountability periodically. 
If a Sponsor representative or designee is present at the time of use, he/she may directly take 
possession of used device(s). All devices will be returned to the Sponsor after the study is complete. 
12.  Device Deficiencies and Malfunctions 
Throughout the study, the Investigator and study staff will report and document all device deficiencies 
and malfunctions related to the identity, quality, durability, reliability, safety or performance of the 
device.  This includes reporting of device deficiencies/malfunctions that did not lead to an AE but 
could have if: 1) suitable action had not been taken, 2) intervention had not been made, or 3) 
circumstances had been less fortunate.  If possible, the Investigator should return devices suspected 
of deficiency or malfunction to the Sponsor for analysis. 
13.  Ethical and Regulatory Considerations 
13.1. Compliance with Good Clinical Research Practice 
This study will be conducted in compliance with the principles of the Belmont Report, the 
Declaration of Helsinki, with the current Good Clinical Practice (GCP) guidelines and with other 
applicable regulations. The Investigator and all study staff will conduct the study in compliance 
with this protocol. Voluntary informed consent will be given by every subject prior to the initiation 
of any study-related procedures. The rights, safety and well-being of the study subjects are the 
most important considerations and prevail over the interests of science and society. All personnel 

 
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involved in the conduct of this study must be qualified by education, training and experience to 
perform their assigned responsibilities. 
13.2. Confidentiality of Data 
All information and data sent to the Sponsor, Contract Research Organizations, or the 
Independent Medical Reviewer concerning subjects or their participation in this study will be 
considered confidential.  All data used in the analysis and reporting of this evaluation will be 
used in a manner without identifiable reference to the subject.  The investigator consents to 
visits by the staff of the Sponsor and its authorized representatives and the U.S. Food and Drug 
Administration or any other governmental body to review the study subjects’ medical records 
including any test or laboratory data. 
13.3. Institutional Review Board (IRB) and Informed Consent 
Before study initiation, the Investigator must have written and dated approval from the IRB for 
the protocol, consent form, subject recruitment materials/process (e.g., advertisements), and any 
other written information to be provided to subjects. The Investigator should also provide the IRB 
with a copy of the product labeling, information to be provided to subjects and any updates. The 
Investigator will submit documentation of the IRB approval to the Sponsor. Copies of all 
correspondence with the IRB regarding this study must be sent to the Sponsor. 
The IRB-approved consent form must include all elements required by FDA, state, and local 
regulations, and may include appropriate additional elements. 
The Investigator/designee will explain the study to each potential subject and the subject must 
indicate voluntary consent by signing and dating the approved informed consent form. The 
Investigator must provide the subject with a copy of the consent form in a language the subject 
understands. The Investigator will maintain documentation that informed consent was obtained 
prior to the initiation of any study-specific procedures. 

 
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Withdrawal of IRB approval of the Investigator’s part in the investigation must be reported to the 
Sponsor within 5 working days. 
13.4. Protocol Compliance 
The Investigator will comply to the extent possible with the IRB-approved protocol.  All deviations 
from the protocol must be documented.  The Investigator will notify the Sponsor immediately if a 
deviation from the protocol was required to protect subject safety.  
13.5. Protocol Revisions 
Revisions to the study protocol can be made only by the study Sponsor. A revised protocol can be 
put into place only after governing IRB approval.  All administrative letters must be submitted to 
the IRB for their information.  
New or altered consent forms required by the IRB due to a protocol change must be signed by all 
subjects currently enrolled in the study and must be used for any subsequent subject enrollment. 
13.6. Study Monitoring 
Representatives of the Sponsor will visit all study sites to perform monitoring and data 
management functions, and provide participating sites with relevant contact information, as 
necessary.  Study monitors may change periodically over the course of this study.  All monitors will 
be qualified to perform their assigned responsibilities, and participating investigators/site 
personnel will be notified of any changes as they occur.  All Study monitors will be blinded to Phase 
1 treatment allocation. 
On-site and/or remote monitoring of all participating sites will be frequent enough to assure 
continued acceptability of the data by assessing site compliance with the study protocol, 
adherence to data collection procedures, and maintenance of study records.  Scheduled site visits 
will include, but are not limited to, the following:  

 
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• Site initiation visit: prior to enrolling subjects, an on-site or remote initiation visit will be 
conducted by clinical study personnel to review this study protocol and discuss eCRF 
completion and transmittal procedures.  Alternatively, a meeting may be conducted for several 
sites at a common location. 
• Interim monitoring site visit: on-site and/or remote monitoring visits will be conducted at all 
sites to assess the progress of the study and identify any concerns that result from review of 
the study records, study management documents, or subject informed consent documents.  
To assure the integrity of the data, a representative number of individual subject records and 
other supporting documents will be compared to eCRFs completed at the site to determine 
that: 
o The study protocol is being followed, and only eligible subjects are being enrolled; 
variances, if they occur, are recorded and reported as appropriate. 
o Informed consent is properly documented.  
o Adverse events are being reported appropriately. 
o Information recorded on eCRFs is complete, accurate and legible. 
o Subjects failing to complete the clinical study and the reason for failure are properly 
recorded. 
• Final monitoring/Close-out site visit: a final visit to participating sites may be made by the study 
monitor, if necessary. Any ongoing responsibilities will be discussed with the investigator 
and/or site personnel as appropriate. 
At the close of the study at an investigational site, appropriately trained personnel appointed by 
the Sponsor will perform a close-out process via the telephone or on-site.  The purpose of this visit 
is to collect all outstanding study data documents, ensure that the investigator's files are accurate 
and complete, review record retention requirements, ensure final accounting of all investigational 
devices shipped to the investigator, provide for appropriate disposition of any remaining supplies, 

 
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and ensure that all applicable requirements are met for the study.  The observations and actions 
made during the intervention will be documented and communicated to the investigator. 
Representatives of government regulatory authorities may also evaluate the study records, source 
documents, Investigator, study staff and facilities. 
The Investigator should immediately notify the Sponsor of any audits of this study by any 
regulatory agency, and must promptly provide copies of any audit reports. 
13.7. 
Safety Reporting 
The Sponsor is responsible for ongoing safety evaluation in this study protocol.  Sponsor activities 
regarding safety include: 
• classification of all AEs 
• review of all AEs reported in the study 
• confirm site’s classification of AEs in terms of severity and relatedness to the study device 
• review of severity and relatedness with the study Investigator, especially when there is 
disagreement between the Investigator and the sponsor 
• review of device deficiencies and malfunctions, including determination and documentation 
of whether deficiencies/malfunctions could have led to an SAE 
• ensuring the reporting of all SAEs and device deficiencies/malfunctions that could have led to 
an SAE to the IRB and, if required, regulatory authorities in a timely fashion 
• informing all site Investigators in writing of all SAEs at all sites in a timely fashion 
• updating the risk analysis and assessment of corrective or preventive actions potentially 
required as a result of new information obtained in the investigation 
 
The Sponsor will evaluate all serious adverse events against US reporting requirements (Medical 
Device Reporting, 21 CFR 812) and Medical Device Directive (vigilance incident reporting) as per 
its standard operating procedures.  The Sponsor will investigate each SAE to determine whether 
the event represents an unanticipated serious adverse device effect (USADE, see Section 7).  The 

 
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Sponsor will report any event to regulatory authorities, Investigators and reviewing IRBs/ECs as 
necessary. If an investigation shows that a USADE presents an unreasonable risk to subjects, the 
Sponsor will terminate all investigations or parts of investigations presenting that risk as soon as 
possible. The Sponsor will only resume a terminated investigation after corrective actions have 
taken place, site Investigators are informed and IRBs/ECs have been notified and given approval 
to resume the study. 
13.8. 
Electronic Case Report Forms/Electronic Data Capture 
The study will use an electronic data capture (EDC) system to implement electronic case report 
forms (eCRF).  The system will allow compliance with 21 CFR 11 Electronic Signatures.  All CRF’s 
are housed in the EDC system.  The Investigator and Coordinator will be trained in use of the eCRF 
prior to study initiation. Retraining in use of EDC can occur at any time. The EDC system will be 
validated prior to use and after any modification is made. Each eCRF will be designed to 
accommodate the specific features of the trial design.  Modification of a eCRF will only be made if 
deemed necessary by the study sponsor. 
An eCRF is required and should be completed for each included subject. The Investigator has 
ultimate responsibility for the collection and reporting of all data entered on the eCRFs and any 
other data collection forms (source documents) and ensuring that they are accurate, 
authentic/original, attributable, complete, consistent, legible, timely (contemporaneous), 
enduring and available when required. The eCRFs must be signed by the investigator to attest that 
the data contained therein are true.  
The site will be provided with general eCRF Completion Guidelines which will assist in data entry 
and data issues/questions. All persons allowed to enter or change eCRF data must appear on the 
Delegation of Responsibilities Log.  

 
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The Sponsor will remotely monitor the eCRFs to identify possible data errors.  The system will have 
a query mechanism whereby the site Coordinator can respond to Sponsor queries. All data 
discrepancies will be resolved prior to database lock.  
13.9. 
Quality Assurance Audits 
Sponsor representatives or designees may conduct site quality assurance (QA) audits during the 
study.  The Investigator must agree to provide the auditor with direct access to all relevant 
documents and discuss any findings with the auditor. 
In the event of an inspection by the FDA or other regulatory authorities, the Investigator must give 
the inspector direct access to relevant documents and to discuss any findings with the inspector. 
The Investigator must notify Sponsor in the event of a FDA site audit. 
13.10. 
Records Retention 
The Investigator must maintain all study records (including device disposition, informed consents, 
source documents, correspondence, regulatory documents, contracts etc.) for at least 2 years 
after study completion.  At the Investigator’s discretion, all records may be sent to the Sponsor for 
permanent storage. 
The Investigator must contact the Sponsor or designee prior to destroying any records associated 
with this study.  If the Investigator withdraws from the study, all study-associated records must be 
transferred to a mutually agreed upon designee. Written notification of such a transfer must be 
given to the Sponsor or designee. 
13.11. 
Publication and Reporting of Study Results 
The study will be registered with clinicaltrials.gov before the first subject is enrolled.  Study results 
will be documented in a study report that will be signed by Sponsor representatives and by each 
Investigator who enrolls subjects in the study, unless otherwise noted.  

 
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If the results of this study will be published, all standard editorial and ethical practices, will be 
followed. Results from multi-center studies must be published or presented at congresses only in 
their entirety with data pooled from all centers. Individual Investigators may not publish data from 
individual centers, unless granted specific written permission from the Sponsor to do so. 
The list of authors of any formal publication or presentation of study results may include, as 
appropriate, representatives of the Sponsor. 
14.  Personnel Responsibilities 
14.1. 
Investigator responsibilities: 
 
Investigators are responsible for ensuring the investigation is conducted according to all signed 
agreements, the study protocol, and applicable regulatory agency regulations (21 CFR 812), which 
include:  
a) Permit monitor inspection of facilities and records. 
b) Permit FDA and other government health authorities’ inspection of facilities and records. 
c) Submit protocol and informed consent to IRB and await approval. 
d) Submit proposed amendments to protocol and informed consent to IRB and await approval, 
unless the change reduces the risk to subjects. 
e) Obtain informed consent of subjects. 
f) Implement study in accordance with protocol. 
g) Complete case report forms.  
h) Record and explain deviations from protocol and report to monitor. 
i) Submit annual progress reports, final reports, and adverse effect reports to IRB and sponsor. 
j) Record the receipt, disposition, and return of study devices. 
k) Refrain from promoting study or study articles in such a way that the potential subject will be 
biased in his/her responses. 
l) Maintain medical histories of subjects. 

 
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m) Retain records for two years following FDA approval of marketing application. 
14.2. 
Sponsor Responsibilities 
Listed below are the Sponsor’s responsibilities for this study. 
a) Assure IRB approval of protocol and informed consent is obtained. 
b) Select and train monitors. 
c) Select investigators. 
d) Train investigators in device use. 
e) Obtain Agreement Letter and curriculum vitae and proof of appropriate licensure of investigator 
and other study staff. 
f) Control shipment of investigational devices. 
g) Conduct day-to-day administration of study. 
h) Investigate unanticipated, device related adverse effects. 
i) Document protocol deviations and violations. 
j) Obtain statement of financial disclosure. 
k) Will appoint trained and qualified representative(s) to perform initial pre-screening. 
l) May supervise device calibration. 
15. Investigator Qualifications 
Investigators must have an active license and board certification and experience in the treatment of 
RLS, as documented on their Curriculum Vitae and/or in a statement of the investigator’s relevant 
experience, including dates, location, extent, and type of experience. Each Investigator must undergo 
training conducted by the Sponsor, on the study device prior to study initiation. 
16. Study Procedures 
16.1. 
Overview 
The study consists of 8-weeks of in-home treatment, consisting of a 4-wk sham-controlled phase 
(Phase 1) followed by a 4-wk open-label active treatment phase (Phase 2).  In-person visits are 
scheduled at the start and end of each phase (Days 0, 28, 56) and at Day 14.  Remote follow-ups – 

 
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calls and/or video calls – are scheduled at additional timepoints throughout both phases to assess 
interim response to treatment, as discussed in Section 16.13 below.  
16.2. 
Recruitment 
Among applicants, subject eligibility will be determined based on the inclusion and exclusion criteria 
discussed above.  A pre-screening call will be completed prior to the first in-person visit (and thus prior 
to consent) to exclude most ineligible applicants prior to the in-person visit.  The pre-screening call  
will be performed by a sponsor-appointed representative.  Eligibility will be contingent on scheduling 
constraints, such as research facility and research staff availability. 
16.3. 
Informed consent Process 
All subjects must be provided a consent form describing the study with sufficient information for 
subjects to make an informed decision regarding their participation. Subjects must sign the IRB 
approved informed consent prior to participation in any study specific procedure, with the exception 
of pre-screening. The subject must receive a paper or electronic copy of the signed and dated consent 
document. The signed copy of the consent document must be retained in the study binder in paper 
or electronic format. The schedule of visits and procedures is provided in Table 3.   
16.4. 
Screening 
Potential subjects will be screened for eligibility based on the criteria in Section 7 above.  Device 
calibration (Section 16.5 below) will be part of the screening process, consistent with Exclusion 
Criterion #18.  A potential subject who signs the study consent and is eligible will be assigned a study 
ID number, will be considered enrolled, and will count towards the study’s sample size.  Potential 
subjects who fail Exclusion Criterion #18 and experience an adverse event (AE) during device 
calibration will be assigned a study ID for the purpose of tracking this AE but will not be randomized 
to a treatment arm and will not count towards the study’s sample size. 
16.5. 
Device calibration  
During screening, the stimulation intensity of the investigational device will be calibrated separated 
for each leg (left and right), using the demo calibration kit provided by the sponsor.  If the subject 
does not fail Exclusion Criterion #18 during calibration the subject will be randomized within the EDC 
system, the calibrated values will be programmed into the investigational device kit that corresponds 

 
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to the randomization number generated.  The calibration process is designed to identify the maximally 
effective settings that are comfortable for each subject.  The sponsor may administer the calibration 
and/or assist in administering the calibration. 
16.6. 
Baseline Assessments  
At study entry, the following assessments are completed: IRLS [12], Subject characterization, Medical 
history, Refractory characterization, MOS-Sleep (Medical Outcomes Study Sleep Scale [13]), and 
Concomitant medications.  If the screening process takes multiple days, the IRLS and MOS-Sleep must 
be administered on the final day of screening. 
16.7. 
Randomization 
Following consent and enrollment, authorized site staff will be provided with each subject’s assigned 
study device kit number by the EDC system during the randomization process. The site staff will record 
the assigned randomization number on both the device kit label and the subject’s source documents.  
The site staff will also record the randomization assignment in the Device Accountability Log.  Subjects 
will be randomized in a 1:1 to either: 
• NTX100 programmed to ACTIVE mode 
• NTX100 programmed to SHAM mode 
Randomization assignments will be stratified by study center with randomly chosen block sizes of 4 
or 6. Small but randomly determined block sizes preserve treatment assignment balance within study 
center while maintaining assignment unpredictability. Any Investigator who is discovered to tamper 
with randomization will be immediately terminated from the study.   
16.8. 
Device training 
Following randomization, subjects are trained on proper usage of the device, including positioning of 
the devices on their legs.  Instrument(s) designed for marking the human skin (body-marking pen or 
temporary tattoo) may be employed to mark the locations of electrode placement.  Device calibration 
may be adjusted during device training based on subjective feedback from the subject. 
16.9. 
Transition to open-label active treatment 

 
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At Day 28, all subjects will receive NTX100 programmed to ACTIVE mode for use throughout Phase 2 
and will be instructed that they will now be receiving Active treatment.  Neither the research staff nor 
the subjects are retrospectively informed of the mode used during Phase 1.   
16.10. 
Study Treatment Description 
Study subjects are instructed to self-administer treatment nightly as needed – typically after RLS 
symptoms start and before RLS symptoms become severe.  The instructions for timing of device use 
may be adjusted based on the timing of RLS symptoms experienced by the subject.  Once activated, 
a single session of treatment may run for approximately 30 minutes and then turn off automatically.  
Up to 120 total minutes per night may be used.  If device battery life limits the number of uses per 
night, the following two timings of use may be prioritized: (1) at bedtime, to reduce symptoms and 
thus help with sleep initiation, and (2) when waking up in the middle of the night, to reduce 
symptoms and thus help with sleep re-initiation.  Device intensity is typically set to the calibrated 
levels, but intensity may be increased if RLS symptoms are especially severe or decreased such as if 
RLS symptoms are mild. 
16.11. 
Concomitant Medications and Treatments 
Study subjects are instructed to maintain a stable dose and schedule of all concomitant medications 
and treatments for RLS and of all concomitant medications and treatments that affect RLS symptoms, 
including antidepressants, sleep medications, or sedative antihistamines.  Concomitant medications 
and treatments are tracked throughout the study based on subject reported data.   
16.12. 
Leg movement data collection 
The NTX100 Neuromodulation System may have the capability to collect data on leg movements, such 
as by using accelerometers and/or gyroscope sensors, while the subject is wearing the devices.  These 
data may be collected during this study and used for subsequent analysis and development. 
16.13. 
Evaluation and study assessment schedule 
The following evaluation calls and/or visits are scheduled, as outlined in Table 3 below. A window of 
+/- 2 days may be utilized on office follow-ups and a window of +/- 1 day for any phone follow-up, as 
needed.   

 
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Phase 1 -  
Evaluation 1: Office visit for enrollment, including consent, screening, device calibration, 
randomization and training on device usage.  This may involve a single visit or multiple visits.   
Evaluation 2: (3-days after Eval. #1) Phone follow-up to assess NTX100 use and assess the 
occurrence of adverse events.   
Evaluation 3: (7-days after Eval. #1) Phone follow-up to assess RLS symptoms, NTX100 use and 
assess the occurrence of adverse events. 
Evaluation 4: (14-days after Eval #1) Office follow-up to assess RLS symptoms, NTX100 use, and 
assess the occurrence of adverse events and/or changes to daily medications. 
Evaluation 5: (21-days after Eval. #1) Phone follow-up to assess RLS symptoms, NTX100 use and 
assess the occurrence of adverse events. 
Evaluation 6: (28-days after Eval #1) Office follow-up to assess RLS symptoms, NTX100 use, and 
assess the occurrence of adverse events and/or changes to daily medications. 
Phase 2 - 
 
Evaluation 7: (3-days after Eval. #6) Phone follow-up to assess NTX100 use and assess the 
occurrence of adverse events.   
Evaluation 8: (7-days after Eval. #6) Phone follow-up to assess RLS symptoms, NTX100 use and 
assess the occurrence of adverse events. 
Evaluation 9: (14-days after Eval #6) Phone follow-up to assess RLS symptoms, NTX100 use, and 
assess the occurrence of adverse events and/or changes to daily medications. 
Evaluation 10: (21-days after Eval. #6) Phone follow-up to assess RLS symptoms, NTX100 use and 
assess the occurrence of adverse events. 
Evaluation 11: (28-days after Eval #6) Office follow-up to assess RLS symptoms, NTX100 use, and 
assess the occurrence of adverse events and/or changes to daily medications.  
Evaluations 1, 4, 6, and 11 are intended to be in-person and all other Evaluations are designed to be 
remote interactions (calls or video calls).  Evaluation 4 may be replaced by remote interactions to the 
extent needed to reduce risk to subjects and/or to the extent that technology allows for remote 
interactions.  

 
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The schedule of assessments are shown in Table 3 below.  In addition to these assessments, subjects 
will complete a Daily Questionnaire each day throughout the 8-wk study duration.  Additionally, the 
devices may automatically log quantitative compliance, usage data, and leg movement data 
throughout the duration of the study. 
TABLE 3: SCHEDULE OF ASSESSMENTS 
 
  
 * If EVAL 1 spans multiple days, Day 0 refers to the final day of EVAL 1. 
 
16.14. 
Administration of assessments 
o PGI-I (Patient Global Impressions – Improvement Scale). The subject and not the examiner 
(site staff) should make the ratings, but the examiner should be available to clarify any 
misunderstandings the subject may have about the questions. The examiner should mark the 
subject’s answers on the form. 
o CGI-I (Clinical Global Impressions – Improvement Scale).  The CGI-I is completed by the 
Investigator after reviewing the subject’s PGI-I response and conducting a short interview with 
the subject regarding their RLS symptoms over the past week compared to baseline.  The 
Investigator will not be permitted access to the subject’s IRLS responses. 

 
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o Refractory categorization.  The refractory categorization form should be completed by the 
Investigator, within 72 hours of EVAL 1. 
o IRLS. The subject and not the examiner (site staff) should make the ratings, but the examiner 
should be available to clarify any misunderstandings the subject may have about the 
questions. The examiner should mark the subject’s answers on the form. 
o MOS-Sleep.  The subject and not the examiner (site staff) should make the ratings, but the 
examiner should be available to clarify any misunderstandings the subject may have about the 
questions. The examiner should mark the subject’s answers on the form. 
o Blinding assessment.  The subject and not the examiner (site staff) should make the ratings, 
but the examiner should be available to clarify any misunderstandings the subject may have 
about the questions. The examiner should mark the subject’s answers on the form. 
o The Daily Questionnaire will be completed by the subject.   
o Subject characterization will be completed by the examiner (site staff) based on information 
from the subject.   
o Medical history will be completed by the examiner (site staff) based on information from the 
subject.   
o For the Weekly questionnaire, the subject and not the examiner (site staff) should make the 
ratings, but the examiner should be available to administer the questions and clarify any 
misunderstandings the subject may have about the questions. The examiner should mark the 
subject’s answers on the form. 
16.15. 
Study Exit 
Study exit will occur at the conclusion of Eval #11.  At study exit, the Investigator/coordinator will 
complete the study exit eCRF.  Adverse events unresolved at study exit will be followed by the 
Investigator until resolution occurs or at least 60 days after the subject’s participation in the study is 
complete. 
16.16. 
Subject Discontinuation 
A subject may be removed from the study prior to completion for any of the following reasons: 
• Voluntary withdrawal of consent 

 
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• Adverse event preventing further study participation 
• Investigator believes risk of further subject participation outweighs benefit 
• Persistent non-compliance or lost to follow-up 
• Pregnancy 
• Subject no longer meets inclusion criteria 
• Subject makes a significant change to dosage of medications known to interfere with sleep or 
RLS symptoms, including sleep medications, antidepressants, sedative antihistamines. 
The Investigator or research staff will complete a study exit form in the eCRF for any subject who 
prematurely discontinues from the study.  If discontinuation was the result of an AE, the AE will also 
be recorded in the eCRF. 
Upon discontinuation, subjects will receive partial compensation commensurate with their completed 
Phases. 
16.17. 
Study Termination 
The Sponsor may terminate the study as a whole or at individual study sites under the following 
circumstances: 
• Suspicion of risk to subjects, including occurrence of high rate of known AEs or unexpectedly 
high rate of unexpected AEs 
• Poor site compliance with the study protocol 
• Inadequate site enrollment 
• Obtaining new scientific knowledge that shows that the study is no longer valid or necessary 
• Persistent non-compliance with IRB or regulatory requirements 
• Persistent failure to comply with obligations arising from the clinical trial agreement 
• Other business reasons (e.g., insolvencies or business entity liquidation) 
The sponsor will document reasons for study suspension and notify relevant site Investigators and 
governing IRBs.  If suspension occurred because of a safety issue, all Investigators will be notified. 
When terminating the study, the sponsor and Investigator will assure that adequate consideration is 
given to the protection of the subjects’ interests.   

 
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17.  Study Endpoints  
17.1. 
 Efficacy 
17.1.1. Primary Efficacy Endpoint 
The primary outcome measure will be responder rate on the CGI-I scale at Week 4 of Phase 1 
relative to Baseline (study entry) and compared between the study arms.   
 
Responder rate for the 7-point CGI-I scale will be defined as the proportion of responses of “Much 
Improved” or “Very Much Improved”.   
17.1.2. Key Secondary Efficacy Endpoints 
For all subjects: 
1. PGI-I responder rate (defined as for CGI-I) at Week 4 of Phase 1 relative to Baseline and 
compared between study arms. 
2. Mean reduction in IRLS score at Week 4 of Phase 1, relative to Baseline and compared 
between study arms. 
3. Mean reduction in MOS-II (Medical Outcomes Study Sleep Problems Index I) score at 
Week 4 of Phase 1, relative to Baseline and compared between study arms. 
4. Mean reduction in MOS-II (Medical Outcomes Study Sleep Problems Index II) score at 
Week 4 of Phase 1, relative to Baseline and compared between study arms. 
5. Mean CGI-I score at Week 4 of Phase 1 relative to Baseline and compared between study 
arms. 
Definition and instructions for calculation of the Medical Outcomes Study Sleep Problems Index I 
and II are described in [13]. 
17.1.3. Efficacy Analysis 
A Statistical Analysis Plan (SAP) will be developed prior to breaking the blind, which will include a 
plan for efficacy analysis.  Briefly, the Intent to Treat population may be used as the primary 
analysis population for all efficacy analyses, the Per Protocol population may be used as 
supportive, and missing data may be addressed with the use of multiple imputation.  Appropriate 
statistical techniques will be employed to test statistical significance.  If there is success on the 
primary endpoint, then secondary endpoints may be tested in order, according to the fixed-
sequence method, until failure.   

 
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The analysis cohort for the primary efficacy endpoint are subjects who are randomized, undergo 
the assigned treatment, and have complete, evaluable Day 28 data. Subjects will be excluded from 
the Per Protocol analysis if one or more of the following occurs during or before the Phase of the 
study corresponding to the endpoint: 
1. Dropout or removal from the study. 
2. Incomplete or missing data for the endpoint. 
3. Clinically significant change in dose or schedule of medication that affects RLS 
symptoms (IC #8) or major lifestyle changes that affect RLS symptoms to a clinically 
significant degree (IC #9). 
4. New medical information available after randomization indicates an exclusion criterion. 
5. Other protocol deviation occurs that is deemed clinically significant by the investigator.   
Subjects will also be excluded from the Per Protocol analysis if one or more of the following 
occurs during the Phase of the study corresponding to the endpoint: 
6. Device usage at or after bedtime on fewer than two-thirds of the nights with RLS 
symptoms at or after bedtime during the Phase, as reported by the subject on the Daily 
Questionnaire assessments. 
7. Missing* two or more follow-ups during the Phase (*Follow-ups completed out-of-
window are not considered “missing”) 
8. Zero total device uses during the Phase. 
 
17.2. 
Sample Size Justification  
Sample size estimates are based on data from use of an earlier prototype of this investigational device 
in a previously approved protocol (RLS-SNS01).  Based on these data and assuming a 1:1 allocation, 
statistical power of 85%, and 2-sided alpha of 0.05 (or 1-sided alpha of 0.025): 
• For CGI-I responder rate, the sample size needed would be 42 subjects, assuming statistical 
treatment with a two-proportion z-test.  
• For PGI-I responder rate, the sample size needed would be 42 subjects, assuming statistical 
treatment with a two-proportion z-test.  

 
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• For mean reduction in IRLS score, the sample size needed would be 112 subjects, assuming 
statistical treatment with a two-sample t-test. 
• For mean reduction in CGI-I score, the sample size needed would be 36 subjects, assuming 
statistical treatment with a two-sample t-test. 
The maximum of these is 112 subjects.  Previous data with this investigational device are not available 
for the MOS-I or MOS-II.  Based on estimates of a 15% dropout rate, 132 subjects will be enrolled in 
the study to yield approximately 112 completed subjects. 
17.3. 
Safety  
17.3.1.  Safety Endpoints 
The safety endpoint will be a descriptive analysis of adverse events (AEs) for both study arms, 
classified and tabulated by seriousness, relationship to the device, and severity. 
17.3.2. Safety Analysis 
Frequency charts of adverse events occurring at any time during the study will be produced.  The 
proportion of subjects having one or more adverse events between randomization and the Day 28 
will be calculated and compared using a comparison of proportions test.  The proportion of 
subjects reporting on or more adverse events at the Day 56 will tabulated.  Similar analyses will 
be done for SAEs and device-related SAEs. Safety analysis will include all subjects who were 
treated.  A Statistical Analysis Plan (SAP) will be developed prior to breaking the blind, which may 
include additional plans for safety analysis.     
17.4. 
Blinding Analysis 
A Statistical Analysis Plan (SAP) will be finalized prior to breaking the blind, which will include a plan 
for blinding analysis.  The extent to which subjects remained blinded at the end of Phase 1 will be 
assessed by calculating a blinding index based on data from the Blinding Assessment following Phase 
1, in which subjects will be asked what treatment they believe they received.  Further, participants 
who guess that they received “Treatment” or “Sham” (as opposed to “Don’t Know”) will be asked for 
the primary reason for their guess and these results will be analyzed. 
17.5. 
Exploratory Analysis 
Additional statistical analysis that is exploratory in nature may be performed.   

 
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18. Remote procedures 
 
During and after the COVID-19 pandemic, replacing some in-person visits with remote interactions may 
be necessary, for example to reduce risk to subjects and/or to comply with local, state, or federal 
regulations.  In such cases, the study records will indicate which in-person visits were replaced with 
remote interactions.   The allowable study duration may be expanded as needed to allow delay intervals 
for mailing and receiving programmed devices. 
In such cases, one of more of the following approaches may be taken: 
1. Remote calibration and training.  Remote calibration and training, where possible, will be 
coordinated by mailing a calibration/training device to the subject, conducting calibration and 
training via a video call using the calibration/training device, and then mailing programmed 
devices to the subject using the settings determined during the calibration.  Alternatively, the 
same devices used in the study may be used for calibration/training. 
2. Remote follow-up visits.  Remote follow-up visits, where possible, will be completed via call or 
video call, during which the required study assessments will be administered.   
3. Devices may be returned using a pre-paid mailing label, as needed. 
4. Remote consent.  Remote consent procedures will follow the recommendations set forth in the 
“FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health 
Emergency” [14].   For example, or more of the following procedures listed in the guidance will 
be used to confirm consent: 
a. eConsent via a compliant digital platform; 
b. confirmation of consent by an impartial witness via three-way call or video conference; 
c. remote explanation of consent followed by in-person signature of informed consent 
document (to minimize duration of in-person interaction). 
 
19. References 

 
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1. Allen, R.P. et al. Restless legs syndrome: diagnostic criteria, special considerations, and 
epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at 
the National Institutes of Health. Sleep Med. (2003).  doi: 10.1016/s1389-9457(03)00010-8 
2. 2012 Revised IRLSSG Diagnostic Criteria for RLS. Available at: http://irlssg.org/diagnostic-criteria 
3. Allen, R. P. et al. Restless legs syndrome prevalence and impact: REST general population study. 
Arch. Intern. Med. (2005). doi:10.1001/archinte.165.11.1286 
4. Silber, M.H. Treatment of restless legs syndrome and periodic limb movement disorder in adults.  
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Clinical Trial 
Document #: CT-3 (previously CT-04) 
Rev: 2.0 (Superseded Rev A) 
CC#: 660 
Effective: 6/15/2021 
Investigational Plan, Protocol CT-3 
(Pivotal Trial) 
 
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