Open-label Extension Study to Evaluate Longer-Duration Response to the NTX100 Neuromodulation System for Patients With Medication-Refractory Primary Restless Legs Syndrome (RLS)
Phase: NA
Conditions: Restless Legs Syndrome
Sponsor: Noctrix Health, Inc.

 
Protocol Cover Page 
 
Open-label Extension Study to Evaluate Longer-Duration Response to 
the NTX100 Neuromodulation System for Patients with Medication-
Refractory Primary Restless Legs Syndrome (RLS) 
 
Clinical Trial Identifier: NCT05196828 
 
Document Date: 11/24/2021 
 
 

Clinical Trial 
Document #: CT-4 
Rev: 1.0 
Effective: 11/24/2021 
Investigational Plan, Protocol CT-05 
(Extension Study) 
 
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CLINICAL INVESTIGATIONAL PLAN 
 
Open-label Extension Study to Evaluate Longer-Duration Response to the 
NTX100 Neuromodulation System for Patients with Medication-Refractory 
Primary Restless Legs Syndrome (RLS)  
 
PROTOCOL NUMBER: 
CT-05 
VERSION:  
1.0 
SPONSOR: 
Noctrix Health, Inc.  
5424 Sunol Blvd  
Ste 10-451  
Pleasanton, CA 94566 
804-683-4279 
 
SPONSOR REPRESENTATIVE(S): 
Jonathan Charlesworth, PhD 
VP of Clinical Research 
 
Maggie LeDang 
Clinical Operations Manager 
 
Van Lieou 
Sr. Clinical Project Manager 
 
 
 
 
 
 
 
 
The information contained in this document is confidential and proprietary property of Noctrix  
Health, Inc. 
 

Clinical Trial 
Document #: CT-4 
Rev: 1.0 
Effective: 11/24/2021 
Investigational Plan, Protocol CT-05 
(Extension Study) 
 
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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-4 
Rev: 1.0 
Effective: 11/24/2021 
Investigational Plan, Protocol CT-05 
(Extension Study) 
 
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Table of Contents 
Investigator Study Acknowledgement .......................................................................................................... 2 
Study Design Overview Synopsis .................................................................................................................. 5 
Abbreviations ................................................................................................................................................ 7 
1. 
Background ............................................................................................................................................ 8 
2. 
Regulatory Status ................................................................................................................................ 12 
3. 
Objective .............................................................................................................................................. 12 
4. 
Study Design ........................................................................................................................................ 12 
5. 
Blinding ................................................................................................................................................ 14 
6. 
Duration ............................................................................................................................................... 14 
7. 
Study population overview ................................................................................................................. 14 
7.2. 
Complete list of inclusion criteria (IC) .......................................................................................... 15 
7.3. 
Complete list of exclusion criteria (EC) ........................................................................................ 16 
7.4. 
Definition of RLS Refractory to Medication (IC #2) ...................................................................... 18 
8. 
Investigational Device ......................................................................................................................... 19 
9. 
Risks ..................................................................................................................................................... 22 
10. 
Adverse Events ................................................................................................................................ 22 
11. 
Device Tracking ................................................................................................................................ 26 
12. 
Device Deficiencies and Malfunctions ............................................................................................. 26 
13. 
Ethical and Regulatory Considerations ............................................................................................ 27 
13.1. Compliance with Good Clinical Research Practice ....................................................................... 27 
13.4. Protocol Compliance .................................................................................................................... 28 
13.6. Study Monitoring ......................................................................................................................... 28 
13.7. Safety Reporting ........................................................................................................................... 30 
13.8. Electronic Case Report Forms/Electronic Data Capture .............................................................. 31 
13.9. Quality Assurance Audits ............................................................................................................. 32 
13.10. Records Retention ........................................................................................................................ 32 
13.11. Publication and Reporting of Study Results ................................................................................. 33 
14. 
Personnel Responsibilities ............................................................................................................... 33 
14.1. 
Investigator responsibilities: ........................................................................................................ 33 
14.2. Sponsor Responsibilities .............................................................................................................. 34 

Clinical Trial 
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Effective: 11/24/2021 
Investigational Plan, Protocol CT-05 
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15. 
Investigator Qualifications ............................................................................................................... 34 
16. 
Study Procedures ............................................................................................................................. 35 
17. 
Study Endpoints and Analysis Overview .......................................................................................... 48 
18. 
Remote procedures ......................................................................................................................... 52 
19. 
References ....................................................................................................................................... 53 
 
 
 

Clinical Trial 
Document #: CT-4 
Rev: 1.0 
Effective: 11/24/2021 
Investigational Plan, Protocol CT-05 
(Extension Study) 
 
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Study Design Overview Synopsis 
Title  
Open-label Extension Study to Evaluate Longer-Duration Response to the NTX100 
Neuromodulation System for Patients with Medication-Refractory Primary Restless Legs 
Syndrome (RLS)  
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.   
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 120min per night. 
Study Objective 
To assess longer-duration efficacy, tolerability, and adherence for patients with moderate to 
severe medication-refractory RLS with the NTX100 Neuromodulation System (NTX100).   
Study Population 
This study will enroll adults with primary moderate-severe medication-refractory RLS who 
previously completed the RESTFUL Study (Advarra IRB Protocol #Pro00050412). 
Study Design 
Arm 1 (Direct Roll-Over Extension) – For subjects who successfully complete The RESTFUL 
Study at or after the initiation of CT-05 at a given clinical site.  Arm 1 involves a 24-wk extension 
period of NTX100 device use followed by an 8-wk period without device use. 
Arm 2 (Control Group) – For subjects who successfully complete the RESTFUL Study prior to 
the initiation of CT-05 at a given site or for subjects who choose not to enroll into Arm 1. 
Subjects enrolled in Arm 2 will not receive treatment with the NTX100 device. Arm 2 involves 
follow-up phone calls to access RLS progression and medication usage at 8-wks, 16-wks, and 
24-wks from the last date of RESTFUL study participation.  
Arm 3 (Delayed Extension) – For subjects who successfully complete the RESTFUL Study prior 
to the initiation of CT-05 at a given clinical site. Arm 3 involves a 24-wk extension period of 
NTX100 device use followed by an 8-wk period without device use.  The sponsor will notify 
each site once Arm 3 is open to enroll study subjects for that site.  

Clinical Trial 
Document #: CT-4 
Rev: 1.0 
Effective: 11/24/2021 
Investigational Plan, Protocol CT-05 
(Extension Study) 
 
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Study Duration 
Arm 1: 32-wks, including 24-wk treatment duration and 8 weeks post study follow-up 
Arm 2: 24-wks, with no treatment 
Arm 3: 32-wks, including 24-wk treatment duration and 8 weeks post study follow-up 
Maximum Study 
Duration 
Arms 1 and 2 are expected to be completed within 12 months after the study opens to 
enrollment.  Arm 3, if initiated, is expected to be completed within 24 months after the study 
opens to enrollment. 
Planned enrollment: 
Up to 132 subjects will be enrolled; all subjects who participated in the RESTFUL Study may be 
eligible.  The same subject may be enrolled into both Arms 2 and 3; if so, this subject will count 
only once towards the total of 132. 
Number of Clinical 
Sites 
Up to 7 clinical sites within the United States, all of which participated in the RESTFUL Study.  
Randomization & 
Blinding 
There will be no randomization or blinding. 
If interest exceeds investigational device availability for Arms 1 or 3, eligible subjects at each 
site will be recruited in the order that they completed The RESTFUL Study. 
Primary Efficacy 
Endpoint 
For Arm 1, the primary outcome measure will be responder rate on the CGI-I scale at Week 24 
of Arm 1 relative to entry to the RESTFUL Study.   
 
For Arm 3, the primary outcome measure will be responder rate on the CGI-I scale at Week 24 
of Arm 3 relative to CT-05 study entry.   
 

Clinical Trial 
Document #: CT-4 
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Investigational Plan, Protocol CT-05 
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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 
1. PGI-I responder rate (defined as for CGI-I) at Week 24 of Arm 1 relative to entry to 
The RESTFUL Study. 
2. Mean reduction in IRLS score at Week 24 of Arm 1 relative to entry to The RESTFUL 
Study. 
3. Mean reduction in MOS-II score at Week 24 of Arm 1 relative to entry to The 
RESTFUL Study. 
4. Mean reduction in MOS-I score at Week 24 of Arm 1 relative to entry to The RESTFUL 
Study. 
5. Frequency of RLS symptoms (based on IRLS question #7) at Week 24 of Arm 1 relative 
to entry to The RESTFUL Study. 
Safety Endpoint 
Descriptive analysis of adverse events, classified and tabulated by seriousness, relationship 
to the device, timing, and severity. 
Adherence outcome 
measure 
Ratio of number of days of device use to number of days with RLS symptoms. 
Summary of 
subjective 
assessments 
CGI-I, PGI-I, IRLS, MOS-Sleep, SF-36, Weekly questionnaire, Bi-weekly questionnaire,  
Concomitant medications 
 
 
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 

Clinical Trial 
Document #: CT-4 
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Effective: 11/24/2021 
Investigational Plan, Protocol CT-05 
(Extension Study) 
 
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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 
SF-36 
Serious Adverse Event 
36-Item Short Form Health Survey  
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 
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. 

Clinical Trial 
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Investigational Plan, Protocol CT-05 
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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 
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 

Clinical Trial 
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Effective: 11/24/2021 
Investigational Plan, Protocol CT-05 
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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 
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 

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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 
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. 
1.6. The RESTFUL Study 
The Sponsor of this study previously received IRB approval for “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” 
(Advarra IRB Protocol #Pro00050412), which has the objective of providing comparative evidence 
assessing clinically meaningful benefit in the treatment of patients with moderate to severe 

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medication-refractory RLS with the NTX100 Neuromodulation System.  The enrollment for “The 
RESTFUL study” began in May 2021, and is currently enrolling subjects as of November 2021.  The 
current study is intended as an extension to the RESTFUL Study and thus is limited to subjects who 
previously completed the RESTFUL Study.   
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. The investigational protocol CT-04 uses the same NTX100 Neuromodulation System 
prototype planned for use in this study, which was also approved as an nonsignificant risk device study 
by Advarra IRB on March 25, 2021. 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 assess longer-duration efficacy, tolerability, and adherence for patients with 
moderate to severe medication-refractory RLS with the NTX100 Neuromodulation System (NTX100).   
4. Study Design 
Subjects who have previously completed The RESTFUL Study are consented to one of three Arms, the 
design of which is illustrated in the flowchart below (Figure 1).  Arm 1 is a Direct Roll-Over Extension, 
Arm 2 is a Control, and Arm 3 is a Delayed Extension.  A subject may be asked to participate in Arm 3 
after completing Arm 2. 

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• Arm 1 (Direct Roll-Over Extension) – Arm 1 is only an option for subjects who successfully 
complete The RESTFUL Study after enrollment to CT-05 begins at a given clinical site; Arm 1 
involves a 24-wk extension period of NTX100 device use followed by an 8-wk period without 
device use. 
• Arm 2 (Control Group) – Arm 2 is an option for subjects who successfully complete the 
RESTFUL Study before enrollment to CT-05 begins at a given clinical site or subjects who 
decline to participate in Arm 1. Subjects enrolled in Arm 2 will not receive treatment with the 
NTX100 device.  Arm 2 involves follow-up phone calls to access on RLS progression and 
medication usage at 8-wks, 16-wks, and 24-wks after the end of The RESTFUL Study.  Subjects 
who are consented more than 8-wks after The RESTFUL Study completion will only complete 
the remaining follow-ups (e.g. subjects consented 12-wks after The RESTFUL Study will only 
complete the 16-wk and 24-wk follow-ups). 
• Arm 3 (Delayed Extension) – Arm 3 is only an option for subjects who successfully complete 
The RESTFUL Study before enrollment to CT-05 begins at a given clinical site; like Arm 1, Arm 
3 involves a 24-wk extension period of NTX100 device use followed by an 8-wk period without 
device use.  Enrollment in Arm 3 of the study begins after a fixed delay upon close-out of the 
RESTFUL Study; the fixed delay will be >= 24-wks and <= 52-wks, will be the same value for all 
subjects (+/- 2-wks), and will be determined based on investigational device availability and 
other constraints. The sponsor will notify each site once Arm 3 is open to enroll study subjects 
for that site. 
.   
 
 
 
 
 
 
 
 
 

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Figure 1: Study Design Flowchart 
 
 
5. Blinding 
Arms 1 and 3 will be open label.  The treatment assignment on each device will be set to Active for all 
subjects and subjects will be informed that they are received Active treatment.   
Arm 2 does not involve treatment. 
6. Duration 
The study will be completed approximately 18 months after the study opens to accrual.   
7. Study population overview 
The study population will consist of adults with moderate-severe primary RLS who have previously 
completed The RESTFUL Study.  The following inclusion and exclusion criteria are designed to reduce 
confounding variables and reduce risk.   
 
7.1. Screening process differences for each Arm 

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All subjects were screened for the eligibility criteria in Sections 7.2 and 7.3 upon entry to The RESTFUL 
Study, with the exception of IC #13 and EC #25-27.  The following subset of eligibility criteria will be 
re-assessed at screening for CT-05, to confirm that they still apply: 
• Arm 1: IC #8, 12-13.  EC #7, 11*, 12, 14-17, 19, 21-27. 
* except that acute infections with mild symptoms will not be exclusionary. 
• Arm 2: IC #12-13.  EC #12, 17, 21, 23, 25. 
• Arm 3: IC #3-8, 10, 12-13.  EC #2, 3, 6-12, 14-17, 19-27. 
7.2. Complete list of 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. 
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. 

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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. 
13. Subject previously completed the RESTFUL Study.   
7.3. Complete list of 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).   
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. 

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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 
• 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. 

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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. 
25. Subject was unwilling or unable to follow instructions in the RESTFUL Study, including missing 2 or 
more follow-up evaluations. 
26. Subject failed to properly operate the investigational devices during Weeks 5-8 of the RESTFUL 
Study. 
27. Subject experienced a significantly higher than expected rate of device malfunctions in the 
RESTFUL Study, such that the malfunctions appeared to be directly related to the subject’s pattern 
of use. 
  
7.4. 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.  

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4. The patient lacks sufficient response to medication at the maximum approved or 
recommended dosage.**  
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, 

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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: 
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 

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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 
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 

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Investigational Plan, Protocol CT-05 
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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. 
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 

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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 
Investigator until resolution occurs or at least 30 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 
 
1 Definition from ISO14155:2011 

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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). 
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.* 

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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. 
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, 

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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 
• 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. 
The investigational device may include components that are consumable or semi-consumable and 
may be replaced on a periodic or as-needed basis.  Such device replacement can occur via an in-
person exchange or via delivery to the subject via courier from the site. 
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. 

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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 
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. 

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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. 
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 conduct either on-site or virtual oversite visits for 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 

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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.   
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:  
• 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. 

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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, 
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 

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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 
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).  Data collected throughout the duration of the study will be entered directly into 
the EDC system.  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 
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.  

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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.  
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, 
supporting 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. 

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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.  
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. 

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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. 
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 – device training 
conducted for the RESTFUL Study protocol will satisfy this requirement. 

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16. Study Procedures 
16.1. 
Overview 
Arms 1 and 3 involve a 24-week extension of in-home investigational device usage for subjects who 
previously completed the RESTFUL Study, followed by an 8-week period without investigational device 
usage to assess the progression of RLS following cessation of treatment.  Two separate arms are 
employed to maximize the number of subjects eligible for any extension phase (Arm 1 and Arm 3) 
while also maximizing the number of subjects who can proceed directly to the extension phase (Arm 
1 only).  Notably, in the RESTFUL Study, subjects will have already completed either 4-weeks of device 
usage (Sham  Active) or 8-weeks (Active  Active) depending on randomization.  Since site staff 
were blinded to RESTFUL Study treatment assignment, no procedures in this protocol will be affected 
by RESTFUL Study treatment assignment.   
 
Arm 2 serves as a control arm with matched duration to the 24-week period of investigational device 
usage; this arm is designed to the assess the changes to medication and RLS symptoms that occur 
under the conventional standard of care, in the absence of investigational device intervention. 
Although the duration of Arm 2 states 24-weeks, each subjects participation will vary, since the 24-
week period also includes the time between when the subject exits the RESTFUL study and when they 
enroll in Arm 2 of the CT-05 study. For example, subjects who are consented more than 8-wks after 
RESTFUL Study completion will only complete the remaining follow-ups (e.g. subjects consented 12-
wks after the RESTFUL Study will only complete the 16-wk and 24-wk follow-ups). 
 
16.2. 
Comparison of Study Arms 
Arms 1 and 3 involve identical procedures, with the following exceptions: 
• Eligibility 
a. [Arm 1] Only open to subjects who complete the RESTFUL Study after this protocol 
opens to enrollment at a given site - and thus can directly enter this protocol.   

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b. [Arm 3] Only open to subjects who completed the RESTFUL Study before this protocol 
opens to enrollment at a given site - and thus have some delay before entering this 
protocol).  Subjects who have completed Arm 2 remain eligible for Arm 3.  
• Delay 
a. [Arm 1] There is typically no delay between RESTFUL Study completion and Arm 1 
entry.  A delay of up to 2-days is permitted if needed. 
b. [Arm 3] There is a fixed delay between RESTFUL Study completion and Arm 3 entry.  
The fixed delay will be >= 24-wks and <= 52-wks, will be the same value for all subjects 
(+/- 2-wks), and will be determined based on investigational device availability and 
other constraints.  
• Baseline  
a. [Arm 1] Baseline refers to RESTFUL Study entry (Eval 1 of RESTFUL Study). 
b. [Arm 3] Baseline refers to entry to this protocol (Eval 1 of this protocol). 
• Assessments at Eval 1 
a. [Arm 1] The IRLS and MOS-Sleep data from are not administered at Eval 1, because 
they are administered on the same day at Restful Study Eval 11. 
b. [Arm 3] The IRLS and MOS-Sleep are administered at Eval 1. 
 
Arm 2 differs significantly from Arm 1 and 3: 
• Eligibility 
a. [Cohort 2A] Subjects who completed the RESTFUL Study after this protocol opens to 
enrollment are eligible for Arm 2 only if they decide not to participate in Arm 1.  All 
subjects in this group are first given the choice to participate in Arm 1 without 
knowledge of the alternative Arm 2. 
b. [Cohort 2B] All subjects who completed RESTFUL Study less than 24-wks before this 
protocol opens to enrollment are eligible for Arm 2. 
• Delay 

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a. [Cohort 2A] There is typically no delay between RESTFUL Study completion and Arm 2 
entry.  A delay of up to 2-days is permitted if needed. 
b. [Cohort 2B] There is a variable delay between RESTFUL Study completion and Arm 2 
entry, depending on the time that the subject completed the Restful Study.  Subjects 
will be enrolled either 8-wks, 16-wks, or 24-wks after completion of the RESTFUL Study, 
+/- 1-wk. 
• Completion 
a. Both Cohorts 2A and 2B are completed 24-wks after completion of the RESTFUL Study 
+/- 1-week.  Therefore, the duration of study participation in Arm 2 depends on the 
delay between RESTFUL Study completion and enrollment in this study. 
• Baseline  
a. For both Cohorts 2A and 2B, baseline refers to RESTFUL Study entry (Eval 1 of Restful 
Study). 
 
Table 3.  Comparison of Study Arms 
 
Arm 1 
Arm 2 
Arm 3 
Eligibility 
Later cohort of 
RESTFUL Study 
subjects 
RESTFUL Study 
subjects who don’t 
complete Arm 1 
Earlier cohort of 
RESTFUL Study subjects 
Start date relative to 
RESTFUL Study 
completion 
0* days 
Less than 24-wks 
Fixed delay, >=24-wks 
and <=52-wks 
End date relative to 
RESTFUL Study 
completion 
32-wks 
24-wks 
Variable 
Duration 
32-wks 
up to 24-wks 
32-wks  
Investigational device use Wks 1-24 
None 
Wks 1-24 
Baseline 
RESTFUL Study 
entry 
RESTFUL Study 
entry 
Entry to this study 
* Up to 2 days if needed 
 

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16.3. 
Recruitment 
Enrollment is limited to subjects who have completed the RESTFUL Study and meet the inclusion and 
exclusion criteria in Section 7.  A pre-screening call may be completed to assess eligibility prior to the 
in-person visit and may be performed by a sponsor-appointed representative.  Eligibility will be 
contingent on scheduling constraints, such as research facility and research staff availability. 
16.3.1. Order of recruitment 
For Arm 1, eligible subjects at a given site will be recruited in the order that they complete the 
RESTFUL Study, with the constraint that subjects will only be eligible if they complete the RESTFUL 
Study after enrollment to this study opens at that site. 
For Arm 3, if enrollment or enrollment rate for a specific Arm and/or a specific site is limited – 
such as by device availability, research facility and research staff availability, or other constraints 
– then eligible subjects at a given site will be invited to this study in the order that they completed 
the RESTFUL Study.   
These procedures are intended to minimize selection bias in recruitment.  The actual order of 
enrollment for each Arm may differ depending on the responsiveness of each given subject that 
is invited and the ability of the subject and site to schedule Eval 1 for that subject in a timely 
manner. 
 
16.4. 
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.  The informed consent form will 
clearly indicate the Arm to which the subject is providing consent.  If a given subject completes more 
than one Arm (e.g. Arm 2 followed by Arm 3), the subject will complete a separate consent form prior 
to enrollment in each Arm. 
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 

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retained in the study binder in paper or electronic format. The schedule of visits and procedures is 
provided in Table 4 (Arms 1 and 3) and Table 6 (Arm 2).   
If a study site has a formal process for eConsent, they may elect to obtain informed consent virtually. 
Sites who do not currently have a process may elect to use the eConsent service provided by the EDC 
vendor.  
16.5. 
Screening 
Potential subjects will be screened for eligibility based on the criteria in Section 7 above.  A potential 
subject who signs the study consent and is eligible will be assigned the same study ID number assigned 
to them during the RESTFUL Study, will be considered enrolled, and will count towards the study’s 
sample size.   
16.6. 
Device calibration  
During the RESTFUL Study, the stimulation intensity of the investigational device was calibrated 
separately for each subject and for each leg.  The calibration process is designed to identify the 
maximally effective settings that are comfortable for each subject.  For Arm 1 and Arm 3, the same 
settings from the RESTFUL Study will be used, except in cases where the subject’s responses indicate 
that these intensity levels are too high or too low.  In that case, the calibration process may be 
repeated either in full or in an abbreviated manner.  The sponsor may administer the calibration 
and/or assist in administering the calibration. 
Each time new stimulation units are provided to a subject during this study, such as with replacement 
devices, they must be programmed with the specific calibrated settings corresponding to that subject. 
16.7. 
Baseline Assessments  
Since this is an extension study to the RESTFUL Study, many of the baseline assessments for a given 
subject in Arm 1 and Arm 2 will refer to assessments completed during the RESTFUL Study, including 
the following: IRLS [12], Subject characterization, Medical history, Refractory characterization, MOS-
Sleep (Medical Outcomes Study Sleep Scale [13]), and Concomitant medications.  Subjects who have 
a delay between their participation of the RESTFUL study and the CT-05 Extension Study (e.g. Arm 3 
participants) will have some or all baseline assessment(s) repeated or re-affirmed.  
16.8. 
Device training 

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Subjects will have already received training on device usage in The RESTFUL Study.  For subjects in 
Arm 3, due to the delay between The RESTFUL Study and Arm 3, training reminders may be needed 
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. 
Study Treatment Description 
For Arms 1 and 3 (but not Arm 2), 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. 
16.10. 
Concomitant Medications and Treatments 
Concomitant medications and treatments are tracked throughout the study based on subject reported 
data.  For Arms 1 and 3 (but not Arm 2), 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.   
16.11. 
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. 
16.12. 
Evaluation and study assessment schedule 

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The following evaluation calls and/or visits are scheduled, as outlined in Tables 4 and 6 below. A 
window of +/- 4 days may be utilized on office follow-ups and a window of +/- 2 days for any phone 
follow-up, as needed.   To reduce self-selection bias, is important to incentivize maximal participation 
of subjects from the RESTFUL Study in this study.  One method to incentivize participation is to reduce 
the requirement for in-person visits, which can be especially challenging for subjects who do not live 
within a short distance of the clinical site.   
 
Arms 1 and 3: 
Evaluation 1: In-person visit for enrollment, including consent, screening, and assessments.  For 
Arm 1, consent & screening will typically occur on the same visit as Eval 11 for the RESTFUL Study.  
If the subject’s schedule does not permit completion of assessments during this office visit, then 
these assessments may be conducted via phone follow-up at any time within the 3-days following 
the office visit. 
Evaluation 2: (2-wks after Eval. #1) Phone follow-up to assess RLS symptoms, NTX100 use and 
assess the occurrence of adverse events and/or changes to daily medications. 
Evaluation 3: (4-wks after Eval #1) Phone follow-up to assess RLS symptoms, NTX100 use, and 
assess the occurrence of adverse events and/or changes to daily medications. 
Evaluation 4: (8-wks after Eval #1) In-person visit or Phone call* follow-up to assess RLS 
symptoms, NTX100 use, and assess the occurrence of adverse events and/or changes to daily 
medications.  Device replacement* and device log analysis may occur at this Evaluation, but this 
is not a strict requirement. 
Evaluation 5: (12-wks after Eval #1) Phone follow-up to assess RLS symptoms, NTX100 use, and 
assess the occurrence of adverse events and/or changes to daily medications. 
Evaluation 6: (16-wks after Eval #1) In-person visit or Phone call* follow-up to assess RLS 
symptoms, NTX100 use, and assess the occurrence of adverse events and/or changes to daily 
medications.  Device replacement* and device log analysis may occur at this Evaluation, but this 
is not a strict requirement. 

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Evaluation 7: (20-wks after Eval #1) Phone follow-up to assess RLS symptoms, NTX100 use, and 
assess the occurrence of adverse events and/or changes to daily medications. 
Evaluation 8: (24-wks after Eval #1) In-person follow-up to assess RLS symptoms, NTX100 use, and 
assess the occurrence of adverse events and/or changes to daily medications.  Devices are 
returned at this time. 
Evaluation 9: (32-wks after Eval #1) Phone follow-up to assess RLS symptoms, adverse events, and 
any changes to daily medications.  Study exit occurs at this time. 
 
* See Section 16.13 below for discussion of device replacement and in-person visits. 
 
In addition to these assessments, subjects will complete a Weekly Questionnaire each week 
throughout the 24-wk duration of device usage and a Bi-weekly Questionnaire every 2-weeks from 
Weeks 25-32. 
The schedule of assessments are shown in Table 4 below.  Additionally, the devices may automatically 
log quantitative compliance, usage data, and leg movement data throughout the duration of the 
study. 
 
Table 4.  Schedule of Assessments for Arms 1 and 3 

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Arm 2: 
Evaluation 1: In-person visit or Phone call for enrollment, including consent, screening, and 
assessments.  For Cohort 2A (see Section 16.2), consent & screening will typically occur in-person 
on the same visit as Eval 11 for the RESTFUL Study.  If the subject’s schedule does not permit 
completion of assessments during this office visit, then these assessments may be conducted via 
phone follow-up at any time within the 3-days following the office visit. 
Evaluation 2: (8-wks after completion of the RESTFUL Study) Phone follow-up to assess RLS 
symptoms, any changes to daily medications, and adverse events. 
Evaluation 3: (16-wks after completion of the RESTFUL Study) Phone follow-up to assess RLS 
symptoms, any changes to daily medications, and adverse events. 
Evaluation 4: (24-wks after Eval #1) Phone follow-up to assess RLS symptoms, any changes to daily 
medications, and adverse events.  Study exit. 
Eval 1
Eval 2
Eval 3
Eval 4
Eval 5
Eval 6
Eval 7
Eval 8
Eval 9
Day 0
Wks 1-24
Wks 25-32
Wk-2
Wk-4
Wk-8
Wk-12
Wk-16
Wk-20
Wk-24
Wk-32
In-person
Remote
Remote
Remote
Remote
In-person or 
Remote**
Remote
In-person or 
Remote**
Remote In-person
Remote
Assessment
Completed by
Screening
X
Consent
X
Study entry 
questionnaire
Staff + subject
X
Weekly questionnaire
Subject
X
Biweekly questionnaire
Subject
X
Review weekly 
questionnaire 
responses
Staff
X
X
X
X
X
X
X
ConMeds
Staff
X
X
X
X
X
X
X
X
X
AE Monitoring/Reporting Staff
X
X
X
X
X
X
X
X
IRLS
Staff + subject
X (Arm 3 only*)
X
X
X
X
X
X
X
X
PGI-I
Staff + subject
X
X
X
X
X
X
X
X
CGI-I
Investigator + subject
X
X
X
X
MOS-Sleep
Staff + subject
X (Arm 3 only*)
X
X
X
X
X
X
X
SF-36
Staff + subject
X
X
Device completion 
questionnaire
Staff + subject
X
Study exit questionnaire
Staff + subject
X
Device replacement
Staff + subject
X **
X **
X **
* For Arm 1, data from Eval 11 of the RESTFUL Study will be used, since both Evals typically occur on the same day
** Device replacement may not occur at these specific Evals; device log analysis & sponsor video call will be concurrent w/ 
device replacement
Schedule of assessments - Arms 1 and 3

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As summarized in Table 5, enrollment to Arm 2 will either occur at either 0-wks (EVAL 1), 8-wks (EVAL 
2), 16-wks (EVAL 3), or 24-wks (EVAL 4) after completion of the Restful Study, +/- 6-days.  If enrollment 
occurs at 24-wks, the SF-36 and concomitant medication assessments will only be conducted once. 
Table 5.  Structure of Arm 2 
Delay after RESTFUL study completion 
Evals conducted 
0-wks 
1,2,3,4 
8-wks 
1,2,3,4 
16-wks 
1,3,4 
24-wks 
1,4 
 
 
TABLE 2: SCHEDULE OF ASSESSMENTS FOR ARM 2 
 
 
16.13. 
Device replacement in Arms 1 and 3 
The investigational device may include components that are consumable or semi-consumable and 
may be replaced on a periodic or as-needed basis.  Such device component replacement may occur 
via an in-person exchange or via delivery to the subject.  At entry to Arm 1, subjects may continue 
using investigational device components from the RESTFUL Study prior to replacement – which may 
require one additional visit for in-person exchange or may be conducted via delivery to the subject. 

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Typically, at Evals 4 and 6, stimulation unit replacement will occur and device log data will be 
downloaded to assess quantitative compliance and usage data and follow-up with the subject 
regarding usage data.  To facilitate this process, subjects will be encouraged to attend an in-person 
visit.  For subjects who live further from the site and/or cannot easily travel to the site, replacement 
device components will be delivered to the subject and the subject will return used stimulation units 
to the site for device log data analysis.  For these subjects, the Eval may be split into two parts, where 
the second part is conducted upon receipt of stimulation units at the site and involves a call to follow-
up with the subject regarding usage data. 
Each time new stimulation units are provided to a subject during this study, they must be programmed 
with the specific calibrated settings corresponding to that subject. 
 
16.14. 
Administration of assessments 
o PGI-I (Patient Global Impressions – Improvement Scale). The subject will determine the 
ratings, and the examiner should be available to clarify any misunderstandings the subject may 
have about the questions. The examiner or the subject may 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 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 but will be permitted access to the subject’s PGI-I responses. 
o IRLS. The subject will determine the ratings, and the examiner should be available to clarify 
any misunderstandings the subject may have about the questions. The examiner or the subject 
may mark the subject’s answers on the form. 
o MOS-Sleep.  The subject will determine the ratings, and the examiner should be available to 
clarify any misunderstandings the subject may have about the questions. The examiner or the 
subject may mark the subject’s answers on the form. 

Clinical Trial 
Document #: CT-4 
Rev: 1.0 
Effective: 11/24/2021 
Investigational Plan, Protocol CT-05 
(Extension Study) 
 
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o SF-36. The subject will determine the ratings, and the examiner should be available to clarify 
any misunderstandings the subject may have about the questions. The examiner or the subject 
may mark the subject’s answers on the form. 
o The Weekly Questionnaire will be completed by the subject.   
o The Bi-weekly Questionnaire will be completed by the subject every 2 weeks during Weeks 
25-32 of Arms 1 and 3.  
o Subject characterization will be completed by the examiner (site staff) based on information 
from the subject.  Subject characterization information may be transferred from the database 
for the RESTFUL Study, if such information is available and has not changed. 
o Medical history will be completed by the examiner (site staff) based on information from the 
subject. Medical history information may be transferred from the database for the RESTFUL 
Study, if such information is available and has not changed. 
16.15. 
Study Exit 
Study exit will occur at the conclusion of Eval #9.  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 30 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 
• 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 
• [For arms 1 and 3 only] Subject makes a significant change to dosage of medications known to 
interfere with sleep or RLS symptoms, including sleep medications, antidepressants, sedative 
antihistamines. 

Clinical Trial 
Document #: CT-4 
Rev: 1.0 
Effective: 11/24/2021 
Investigational Plan, Protocol CT-05 
(Extension Study) 
 
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• [For arms 1 and 3 only] Insufficient device availability (see 16.16.1 below) 
16.16.1. 
Discontinuation related to device availability 
As noted in Section 11, the investigational device may include components that are consumable 
or semi-consumable and may be replaced on a periodic or as-needed basis.  In the unlikely event 
that investigational device supply becomes insufficient to replenish the consumable components 
of the devices for all subjects enrolled in the study, enrollment will be paused and device 
replacement will continue in a normal manner until the device supply for the study is exhausted 
(or nearly exhausted).  At that point, remaining subjects will be removed from the study at their 
next scheduled device replacement timepoint.  
Additionally, it is possible that some patterns of device use or misuse may lead to a reduction in 
the functional lifespan of the investigational device below 8-weeks.  If this is suspected for a 
specific subject, that subject may be removed from the study. 
 
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. 
16.6. 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 

Clinical Trial 
Document #: CT-4 
Rev: 1.0 
Effective: 11/24/2021 
Investigational Plan, Protocol CT-05 
(Extension Study) 
 
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• Insufficient availability of investigational devices 
• 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.   
17. 
 Study Endpoints and Analysis Overview 
17.1. Treatment of data from the RESTFUL Study 
CT-05 is an extension of the RESTFUL Study and Arms 1 and 2 involve a direct roll-over from the RESTFUL 
Study into CT-05.  Therefore, data from the RESTFUL Study (CT-04) will be used to define the Baseline for 
Arms 1 and 2 and may be used to define subgroup analyses and demographic characterization. 
17.2. Efficacy 
17.2.1. Primary Efficacy Endpoint 
Arm 1: The primary outcome measure will be responder rate on the CGI-I scale at Week 24 of Arm 1 
relative to entry to the RESTFUL Study.   
Arm 3: The primary outcome measure will be responder rate on the CGI-I scale at Week 24 of Arm 3 
relative to CT-05 study entry.   
Responder rate for the 7-point CGI-I scale will be defined as the proportion of responses of “Much 
Improved” or “Very Much Improved”.   
17.2.2. Key Secondary Efficacy Endpoints 
Arm 1: 
1. PGI-I responder rate (defined as for CGI-I) at Wk-24 relative to entry to the RESTFUL Study. 
2. Mean reduction in IRLS score at Week 24 of Arm 1 relative to entry to the RESTFUL Study. 
3. Mean reduction in MOS-II score at Week 24 of Arm 1 relative to entry to the RESTFUL Study. 
4. Mean reduction in MOS-I score at Week 24 of Arm 1 relative to entry to the RESTFUL Study. 
5. Frequency of RLS symptoms (based on IRLS question #7) at Week 24 of Arm 1 relative to entry to 
the RESTFUL Study. 

Clinical Trial 
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Effective: 11/24/2021 
Investigational Plan, Protocol CT-05 
(Extension Study) 
 
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Arm 3:  
1. PGI-I responder rate (defined as for CGI-I) at Week 24 relative to CT-05 study entry. 
2. Mean reduction in IRLS score at Week 24 of Arm 1 relative to CT-05 study entry. 
3. Mean reduction in MOS-II score at Week 24 of Arm 1 relative to CT-05 study entry. 
4. Mean reduction in MOS-I score at Week 24 of Arm 1 relative to CT-05 study entry. 
5. Frequency of RLS symptoms (based on IRLS question #7) at Week 24 of Arm 1 relative to CT-
05 study entry. 
Definition and instructions for calculation of the Medical Outcomes Study Sleep Problems Index I and II 
are described in [13]. 
 
17.2.3. Efficacy Analysis 
A Statistical Analysis Plan (SAP) will be developed prior to completion of the first subject in Arm 1 or 3, 
which will include a plan for efficacy analysis.  The following analyses are planned: 
• Primary statistical analysis may be conducted separately for subjects in Arms 1 and Arm 3.  
Additional pooled analysis across Arms 1 and 3 may also be conducted. 
 
• Subgroup analysis form Arms 1 and 3 may be conducted based on the following criteria: 
o Responders at Week-8 of The RESTFUL Study, as defined by CGI-I of 1 or 2. 
o Non-responders at Week-8 of The RESTFUL Study, as defined by CGI-I of 3 or above. 
• 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 will be tested in order, 
according to the fixed-sequence method, until failure.  
The analysis cohort for the primary efficacy endpoint are subjects who are enrolled and undergo the 
assigned treatment.  
The Per Protocol analysis will exclude subjects for whom one or more of the following apply: 
1. Dropout or removal from the study. 
2. Incomplete or missing data for the endpoint. 

Clinical Trial 
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Rev: 1.0 
Effective: 11/24/2021 
Investigational Plan, Protocol CT-05 
(Extension Study) 
 
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3. Clinically significant change in dose or schedule of medication that affects RLS symptoms . 
4. New medical information available after randomization indicates an exclusion criterion. 
5. Other protocol deviation occurs that is deemed clinically significant by the investigator.   
6. Device usage at or after bedtime on fewer than two-thirds of the nights with RLS symptoms at 
or after bedtime, as reported by the subject on the Weekly Questionnaire assessments. 
7. Missing two or more follow-ups (Follow-ups completed out-of-window are not considered 
“missing”) 
8. Zero total device uses. 
17.2.4. Additional efficacy analyses 
Comparison of Arm 1 (investigational device) to Arm 2 (control) 
Arm 1 and Arm 2 both cover the same period of time – the 24-wks after completion of the RESTFUL 
Study).  Arm 1 involves continual open-label usage of the investigational device throughout this time 
period, whereas Arm 2 (control) involves no usage of the investigational device.  Comparison of the 
data from these arms will be used to assess how continued use of the devices over 24-weeks impacts 
RLS symptoms, sleep, and medication use relative to the typical standard of care over 24-weeks. 
• For Arm 2, baseline will be defined as entry to CT-04 Restful Study and similar analyses will be 
conducted as in Arm 1.   
• Results from Wk-24 of Arm 2 (no device usage) will be compared to results from Wk-24 of Arm 1 
(device usage), to assess the effect of continued device usage on the following outcomes: 
o Changes in RLS symptoms, as measured by CGI-I, PGI-I, and IRLS 
o Changes in Sleep, as measured by MOS-II and MOS-I 
o Changes in quality of life, as measured by SF-36 
o Changes in the dose and type of concomitant medications prescribed and/or administered to 
treat RLS 
Changes to symptom severity over time 
• Linear regression of PGI-I over all weeks of Active treatment* 
• Linear regression of IRLS over all weeks of Active treatment* 

Clinical Trial 
Document #: CT-4 
Rev: 1.0 
Effective: 11/24/2021 
Investigational Plan, Protocol CT-05 
(Extension Study) 
 
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• Linear regression of Frequency of RLS symptoms over all weeks of Active treatment* (based on 
IRLS question #7) 
• Linear regression of MOS-II over all weeks of Active treatment*  
• Linear regression of MOS-I over all weeks of Active treatment* 
* For Arm 1, this starts at the beginning of Active treatment in the RESTFUL Study.  For Arm 3, this 
starts at entry to Arm 3. 
 
Additional subgroup analyses 
• Subjects assigned to Sham control for Weeks 1-4 of the RESTFUL Study 
• Subjects assigned to Active treatment for Weeks 1-4 of the RESTFUL Study 
 
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 in Arms 1 and 3 reporting one or more adverse events between study entry 
and Week 24 will be pooled and 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 completion of the first subject in Arm 1 or 3, which may include 
additional plans for safety analysis.     
17.4. Compliance 
Compliance will be assessed during the first 24-wks of Arm 1 and Arm 3.  Subjects will be instructed 
to use devices each nights that they report experiencing RLS symptoms.  Therefore, percentage 
compliance with device usage will be calculated using the following formula:  
100%*(nights of compliant use)/(total nights with patient-reported RLS symptoms) 
 

Clinical Trial 
Document #: CT-4 
Rev: 1.0 
Effective: 11/24/2021 
Investigational Plan, Protocol CT-05 
(Extension Study) 
 
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• Nights of compliant use will be measured based on digital tracking of the timing and duration of 
each NPNS device usage.  In cases where digital tracking logs are incomplete or unavailable, the 
data will not be included in the compliance analysis. 
• A “night of compliant use” will be defined as a minimum of 25 minutes of active NPNS stimulation 
between noon and noon during an Assessment week.   
• “Total assessment nights with RLS symptoms” will be defined as the total nights spent by all 
subjects in Assessment weeks when the subject reports RLS symptoms on the Weekly 
questionnaire.   
• If a subject is discontinued from the study for reasons unrelated to subject response to treatment, 
compliance data will only be assessed up until the time of discontinuation.  Such reasons could 
include lack of device availability, personal reasons, or adverse event unrelated to the study 
device. 
17.5. Exploratory Analysis 
Additional statistical analysis that is exploratory in nature may be performed with CT-05 data alone 
and/or with pooled data from CT-05 and from the RESTFUL Study. 
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 

Clinical Trial 
Document #: CT-4 
Rev: 1.0 
Effective: 11/24/2021 
Investigational Plan, Protocol CT-05 
(Extension Study) 
 
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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 
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.  
In: UpToDate, Post, TW (Ed), UpToDate, Waltham, MA, 2020 
5. García-Borreguero, D. & Williams, A. M. Dopaminergic augmentation of restless legs syndrome. 
Sleep Medicine Reviews (2010). doi:10.1016/j.smrv.2009.11.006 

Clinical Trial 
Document #: CT-4 
Rev: 1.0 
Effective: 11/24/2021 
Investigational Plan, Protocol CT-05 
(Extension Study) 
 
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6. Lipford, M.C. and Silber, M.H. Long-term use of pramipexole in the management of restless legs 
syndrome. Sleep Med. 2012; 13: 1280–1285 
7. Hening, W.A. et al. An update on the dopaminergic treatment of restless legs syndrome and 
periodic limb movement disorder.  Sleep (2004). doi: 10.1093/sleep/27.3.560 
8. Cornelius, J.R, Tippmann-Peikert, M., Slocumb, N.L., Frerichs, C.F., Silber, M.H. Impulse control 
disorders with the use of dopaminergic agents in restless legs syndrome: a case-control study. 
Sleep. 2010 Jan;33(1):81-7. 
9. FDA Drug Safety Communication 12-19-2019.  Available at: https://www.fda.gov/drugs/drug-
safety-and-availability/fda-warns-about-serious-breathing-problems-seizure-and-nerve-pain-
medicines-gabapentin-neurontin. 
10. Silber, M. H. et al. The Appropriate Use of Opioids in the Treatment of Refractory Restless Legs 
Syndrome. Mayo Clin. Proc. (2018). doi:10.1016/j.mayocp.2017.11.007 
11. FDA Center for Devices and Radiological Health Guidance Jan 2006.  Information sheet guidance 
for IRBs, clinical investigators, and sponsors: Significant Risk and Nonsignificant risk medical 
device studies.  Available at: 
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126418.pdf 
12. Walters AS, LeBrocq C, Dhar A, et al. Validation of the International Restless Legs Syndrome 
Study Group rating scale for restless legs syndrome. Sleep Med. 2003;4(2):121-132. 
doi:10.1016/s1389-9457(02)00258-7 
13. Hays, R. D., & Stewart, A. L. (1992). Sleep measures. In A. L. Stewart & J. E. Ware (eds.), 
Measuring functioning and well-being: The Medical Outcomes Study approach (pp. 235-259), 
Durham, NC: Duke University Press. 
14. FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health 
Emergency.  Available at: https://www.fda.gov/media/136238/download.