NET Device as a Non-Pharmacological Alternative to Medication for Opioid Withdrawal Symptom Reduction and Abstinence
Phase: NA
Conditions: Opioid Use Disorder
Sponsor: Wayne State University

Protocol Title:  NET Device for Treating Opioid Use Disorder 
 
ClinicalTrials.gov #:  NCT0491660 
 
Date:  September 3, 2022 
 
Content adapted from:  Greenwald MK, Ghosh S, Winston JR (2022) A randomized, sham-
controlled, quintuple-blinded trial to evaluate the NET Device as an alternative to medication for 
promoting opioid abstinence. Contemporary Clinical Trials Communications 30: 101018. PMID: 
36303593; DOI: 10.1016/j.conctc.2022.101018 
 
 
 

 
 
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Methods 
NET Device description 
Stimulation characteristics. The NET Device delivers alternating current via surface electrodes 
placed transcranially (bilaterally) on the mastoid processes (Figure 1). The device delivers multiple 
low-amperage waveforms at controlled frequencies and pulse widths that vary throughout each 
treatment day, with no net-direct current component; this approach differs from single-frequency, 
sinusoidal transcranial alternating current stimulation. Waveshapes were refined across several 
engineering iterations that adjusted for dynamic variations in skin impedance, electrode conductance, 
frequency and pulse-width related sensation, and orthogonal electrode pressure (e.g. from head 
pressure when sleeping), leading to improved rates of patient tolerability.  
Stimulation is continuously available (except when bathing) for up to 7 days via transcutaneous 
electrodes of size approximately 1cm x 2cm. Stimulation output frequency varies from 4 to 3000 Hz 
and pulse width from 7 to 1024 microseconds. Stimulation output current varies from 0 to 3.2 mA 
(peak) into a 15 kOhm load, and output voltage varies from 0 to 44 volts (peak to peak). 
Treatment is self-administered, and participants are instructed that they can control the device 
output intensity and duration according to perceived benefit. 
Possible mechanisms of action. Earlier studies demonstrated that transcranial electrostimulation 
of the type delivered by the NET Device can attenuate the severity of opioid withdrawal [1–5]. Such 
neurostimulation is thought to modulate endogenous opioid, dopaminergic and serotonergic systems 
and the autonomic nervous system [40-42], which are dysregulated in the opioid-dependent state [6–
12]. We hypothesize that self-titrated NET Device stimulation of these multiple interacting 
neurochemical systems may promote neuroplastic changes [13–16] that normalize functioning of these 
systems and support longer-lasting changes in drug-abstinence behavior. Although the mechanism of 

 
 
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action is not well-understood and is a subject for future investigation, treatment duration (< 7 days, 
self-administered) is consistent with FDA-approved percutaneous nerve stimulators, and the outcome 
measurement period (up to 16 weeks from start of treatment) is consistent with results of open-label 
NET pilot studies in Kentucky and Scotland.  
Safety. As a Non-Significant Risk device, FDA does not require submitting an Investigational 
Device Exemption for this study. Safety of the NET Device has not been established for persons who: 
(1) are pregnant, breastfeeding, or <18 years old; (2) have serious heart conditions or a cardiac 
pacemaker; (3) have suffered a stroke, brain tumor, or brain injury; (4) have current epilepsy; (5) are 
suffering serious psychotic illness; or (6) are taking medications such as neurotransmitter blockers. 
Study design 
This ITT, randomized, single-site trial uses a superiority design that compares active treatment 
to sham control. This trial will evaluate efficacy and safety endpoints during opioid discontinuation 
within an inpatient setting, and subsequent outpatient assessment of opioid and non-opioid substance 
use following discharge (primary and secondary endpoints, respectively). Fifty participants will be 
randomized to each of the two treatment arms (active and sham) and prospectively followed. Figure 2 
illustrates the study schema. Figure 3 illustrates the schedule of activities.  
As the platform for this trial, all participants receive treatment as usual (TAU), except MOUD, 
which they choose (as part of informed consent) not to receive as a condition of inclusion in this study. 
Participants could experience clinical deterioration during inpatient discontinuation of illicit opioids, 
prescribed opioid agonist medications (buprenorphine, methadone), and other illicit substances. 
Participants are instructed that device use (active or sham treatment) is self-administered, they may 
discontinue device use at any time and for any reason and can receive TAU for their clinical condition 
including MOUD and comfort medications.  

 
 
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The rationale for the minimum 1-hour device treatment period is to ensure a controlled degree 
of exposure to the device (active or sham) for all participants; based on prior open-label studies, the 
active device produces benefits in about 15-20 min. Completing this 1-hr period triggers study follow-
up assessments. The rationale for the 7-day maximum device treatment period is to limit variability in 
the duration of exposure (to be treated as a covariate in analyses); as Figure 1 indicates, the majority 
of participants stop active device use after about 7 days.  
Randomization and blinding 
The biostatistician block-randomizes assignment of the ITT population to treatment (sham vs. 
active) using a 1:1 allocation ratio and, within each treatment group, stratification by sex (male/female) 
and non-opioid substance use disorder (presence/absence). The master codebook for randomization is 
kept in a secure location at Wayne State University and only the biostatistician and a research assistant 
(backup person) can access it.  
Sham treatment, which controls for placebo effects, is designed to minimize sham recognition 
by the sponsor, principal investigator, participants, research assistants and treatment staff (i.e. 
quintuple blinding). Participants in the active arm receive standard NET treatment. Participants in the 
sham arm receive the same standard NET treatment as the active arm but will receive no electrical 
stimulation (cable is disabled beforehand). Sham credibility is evaluated for both arms based on 
surveys following the 1-hr treatment phase, and daily during device use. A single ‘treatment 
perception’ question asks: “How confident are you that you are receiving the real device treatment and 
not the placebo (sham) treatment?” Three ‘device satisfaction’ questions ask: (1) “How satisfied are 
you with the NET Device?” (2) “How willing are you to use the NET Model 901 Device?" and (3) 
“How willing are you to recommend the NET Model 901 Device to other people undergoing opioid 
discontinuation?”  

 
 
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Active and sham arms will receive identical device care and use instructions, identical 
equipment, attachment methods and locations, and identical daily reviews of device operation, 
electrode attachment, and withdrawal severity. The treatment apparatus presents both active- and 
sham-assigned participants with visual cues from the device’s “heartbeat” indicator (a blinking green 
light-emitting diode which indicates the device is active) during treatment. Research staff instruct each 
participant that the equipment is designed to be self-administered, that s/he can set the level of 
stimulation wherever it is comfortable, that stimulation is not always (and does not need to be) sensate, 
and that device use may be discontinued when s/he feels it is providing no benefit. 
The sham and active interventions both use the NET Device without alteration. The sham 
intervention uses lead wires that have been rendered non-conductive beforehand, preventing any 
electrical stimulation from being delivered to the participant. Before study initiation, the biostatistician 
allocated a random and unique Study Device Number (SDN) to each identical-looking active and sham 
lead wire, applying pre-printed SDN heat shrink. At the study site, the research assistant is notified 
electronically of participant inclusion, and selects a device and lead wires by SDN from a pre-printed 
randomization table for delivery of active or sham treatment. At the end of the study, all lead wires will 
be delivered to the biostatistician for verification against the group assignment by measuring 
conductivity using the sponsor-supplied validation circuit. 
Outcome measures 
During the 12-week outpatient period, participants will be interviewed for safety and efficacy 
endpoints and undergo a remote drug screen. Remote interviews reduce risk of COVID-19 exposure 
for the participant and research assistant, and decrease transportation barriers (increased feasibility). 
Each week, the research assistant hosts a live video call with the participant, and conducts a timeline 
follow-back (TLFB) review of opioid, MOUD, stimulant, sedative, cannabis and alcohol use for each 
of the prior 7 days. At discharge from the inpatient facility, each participant will be given 12 kits (plus 

 
 
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one spare) of the Premier Biotech OralTox OT-80605, an FDA 510(K) cleared 6-panel rapid oral fluid 
drug screen. Each test covers amphetamines and methamphetamine (positive cutoffs = 50 ng/ml), 
opioids and THC (positive cutoffs = 40 ng/ml), oxycodone and cocaine (positive cutoffs = 20 ng/ml). 
Each individually packaged test is sealed in foil and is marked with a lot number and expiration date. 
Each individual test contains a QR code that encodes a unique identification number that will be used 
to validate authenticity and uniqueness of the screen. The participant receives printed and verbal 
instructions for use from the research assistant, is observed during each test, and test results with 
authenticating QR code are captured as an image file by the research assistant and saved for validation. 
In order to conduct this FDA-qualifying study during the COVID-19 pandemic, remote test methods 
were evaluated for use during the outpatient phase. When this study began, FDA had only approved a 
limited selection of oral fluid rapid tests for use in research. The authors selected TLFB self-report as 
the primary source for data, supplemented by such relevant oral fluid tests as were FDA approved. 
The primary efficacy endpoint is each participant’s overall percentage of weekly abstinence 
from illicit opioid use without use of MOUD. This is defined as the percentage of each participant’s 
negative oral fluid samples and self-reports of illicit opioid, methadone, buprenorphine, and naltrexone 
use per week throughout the 12-week outpatient study period. The rationale for choosing this endpoint 
is to perform a rigorous test of the isolated efficacy of NET, with the safety net of allowing (and 
measuring) participants’ use of MOUDs.  
During a given week, oral fluid samples and self/pharmacy reports that both indicate no illicit 
opioid, methadone, buprenorphine, or naltrexone use will be considered “opioid-abstinence without 
MOUD”. Cumulative distribution function, time (days) to first use of illicit opioids, time (days) to first 
use of MOUD, and duration (weeks) of continuous abstinence without MOUD will be evaluated as 
supportive outcomes. Response profiles for each treatment arm are based on each participant’s 
individual rates of weekly illicit opioid or MOUD use, including negative oral fluid results and daily 

 
 
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self (TLFB) of illicit opioid or MOUD use/non-use. Table 1 presents explanatory cases of the primary 
efficacy endpoint measurement. The null hypothesis is that “opioid abstinence without MOUD” will 
not significantly differ between active and sham groups, whereas the alternative hypothesis is that 
“opioid abstinence without MOUD” will be superior in the active (relative to sham) treatment arm. 
The secondary efficacy endpoint is each participant’s percentage of non-opioid drug-free weeks 
during the 12-week outpatient period. Non-opioids assessed include cocaine, sedatives, and stimulants. 
Use of alcohol and cannabis will be measured, but are not included in the secondary efficacy analysis, 
due to their legal status. Response profiles for each arm are based on each participant’s individual rates 
of weekly abstinence data, including negative oral fluid results and daily self-reports of non-opioid 
drug use/non-use (TLFB). 
The secondary safety endpoint is the prevalence of all adverse events (AEs), serious adverse 
events (SAEs), adverse device effects (ADEs), serious adverse device effects (SADEs), unanticipated 
adverse device effects (UADEs), and device deficiencies. 
Supportive and exploratory measures. Treatment retention will be measured throughout the 
inpatient and outpatient phases. Self-stimulation intensity (in 5-min bins), duration, and device on/off 
data from each NET Device are automatically transmitted to a computer server and processed offline. 
Opioid withdrawal symptoms, craving severity, and positive/negative affect are measured daily during 
the first inpatient week. Measures of depression, anxiety and stress, sleepiness, and health-related 
quality of life are obtained at the conclusion of inpatient and outpatient phases. 
Participant selection criteria 
 
Screening includes informed consent, HIPAA authorization, assessment of demographics, 
contact data, pregnancy testing, contraception methods, medical history, and urine drug testing 
(including fentanyl, buprenorphine, and methadone). Assessments are aligned with the treatment 

 
 
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facility’s standard of care such that electronic case report forms (eCRFs) can be rapidly reviewed for 
study eligibility by the remote investigator, given the time-sensitive nature of enrollment.  
 
During the recruitment and informed consent process, participants are repeatedly told they can 
receive FDA-approved MOUD at the treatment facility instead of participating in the study. They are 
also told that upon discontinuation of device stimulation, and/or if they drop out of the study, they can 
receive TAU (including MOUD) at any time. All participants are given a “loss-of-opioid tolerance” 
warning (i.e. stopping opioids leads to reduced tolerance, and subsequent opioid use increases their 
risk of overdose and death), which they must sign. Participants are also given a naloxone kit upon 
discharge from the treatment facility and educated on its use. All of these procedures are documented 
in the medical record and case report forms. 
 
Table 2 presents study inclusion and exclusion criteria. For inclusion, participants ages 18-65 
years old must have current OUD, present in otherwise good health, be seeking opioid discontinuation 
at the treatment facility, self-report that they wish to become/remain abstinent without using MOUD, 
be willing to follow study procedures, provide informed consent and use medically-accepted highly 
effective contraception. An additional criterion (following informed consent) is that device use will not 
begin until the Clinical Opiate Withdrawal Scale (COWS [17]) total score is 13 or greater (at least 
moderate withdrawal); thus, a consented participant could be dis-enrolled if the latter criterion is not 
met. Exclusion criteria include pregnancy or lactation, serious current psychiatric disorder 
(schizophrenia, bipolar) or use of neuropsychiatric medications that may overlap with NET’s proposed 
mechanisms of action (e.g. anxiolytics, antidepressants, anticonvulsants, sedating H1-receptor 
antihistamines, prescription or over-the-counter stimulants), need for detoxification from alcohol or 
benzodiazepines, past 300-day exposure to extended-release buprenorphine, certain chronic illnesses 
(especially seizures), unstable medical conditions, or presence of cardiac pacemaker. 
 

 
 
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Data & safety monitoring 
Oversight of data management and quality assurance is the responsibility of the investigator 
with input from the Study Monitor designated by the sponsor. Trial data are managed with a sponsor-
designed electronic source data system. This system provides source data capture, modification, 
correction and access based on pre-defined roles, e.g. only the investigator can determine 
inclusion/exclusion. Specific eCRF data are exported to a FDA-compliant electronic data capture 
(Advarra) system at Wayne State University, where the biostatistical team manages and analyzes 
outcome measures. There is no data safety monitoring board for this trial. 
Statistical analysis plan 
Sample size determination. Sample size is based on statistical power analyses for the primary 
hypothesis based on single primary outcome (opioid abstinence without MOUD). A conservative 
approach was used to preserve power with a smaller effect size than observed from prior uncontrolled, 
non-blinded intervention studies with the NET Device. Power analyses examined sample sizes 
required to detect clinically meaningful group differences between sham and active groups. This 
represents standardized difference between the two groups after adjusting for the effect of the covariate 
“duration of inpatient residence” (which is capped at 28 days). Sample size determination was carried 
out via simulation in R-software; 5000 iterations were run in which group means were generated using 
a mixed-effect additive model. Sample size is a function of hypothesized effect size (standardized 
group difference) and the sign and magnitude of the regression coefficient (duration of inpatient 
residence). With projected N=100 (enrolled) there will be sufficient power to detect a standardized 
effect size of 0.45 or higher.  
Missing data. In this ITT design, a participant is “included” (becomes part of the evaluable ITT 
data set) when he/she completes 1-hr of device use. We expect only 5% attrition, i.e. for 100 participants 
who complete 1-hr of device use, we expect to consent 105 individuals. A comparable trial of a 

 
 
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percutaneous electrical stimulation device for treating opioid withdrawal symptoms found that 71 of 73 
enrolled participants completed 1-hr of device use, only 2.8% attrition [18]. Table 1 explains how missing 
data are handled, i.e. for the primary efficacy endpoint, missing data are imputed as “not opioid 
abstinent without MOUD”. The definition of the primary endpoint (“opioid abstinence without 
MOUD”) and secondary endpoint (“non-opioid abstinence”) thus covers any intermittent missing 
values and loss to follow-up, and is not expected to impact power of the primary analysis. Premature 
study termination (e.g., death, relocation, or adverse events) may result in missing data, although this 
attrition is expected to be low. The projected sample size (N=125) was increased to cover unforeseen 
events.  
Participant withdrawal. Participants can withdraw from the study at any time on request. 
Discontinuation of device use prior to completing the minimum 1-hr treatment period constitutes 
withdrawal from the study. The investigator may discontinue or withdraw a participant from the study 
for the following reasons: (1) significant study intervention non-compliance; (2) if any clinical adverse 
event (AE), laboratory abnormality, or other medical condition or situation occurs such that continued 
participation in the study is not in the best interest of the participant; (3) disease progression which 
requires discontinuation of the study intervention; (4) if the participant meets an exclusion criterion 
(either newly developed or not previously recognized) that precludes further study participation; or (5) 
participant is unable to receive treatment following enrollment. 
Participants who sign the informed consent form and are randomized but do not receive the 
study intervention will be replaced. Participants who sign the informed consent form, are randomized, 
receive the study intervention, and subsequently withdraw or are withdrawn, will be replaced. 
Participants who withdraw from the study will receive TAU as defined by treatment staff (who 
are independent of the research staff), where such care may include MOUD.  

 
 
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Lost to follow-up. A participant is considered lost to follow-up if s/he becomes unavailable for 
all video assessments following discharge from the inpatient environment.  
Populations for analysis. The ITT analysis dataset and the safety analysis dataset will contain 
all randomized participants. The per-protocol analysis dataset will contain the subset of the ITT dataset 
who: (1) present with a COWS score of moderate or above; (2) receive at least 1 hr treatment from the 
device; and (3) complete at least one post-discharge video interview. 
Efficacy endpoints. The primary analysis will assume that data came from a mixed-effect linear 
model. Each model will include a random intercept, fixed effect for treatment, participant-specific 
random effect and covariate corresponding to duration of inpatient residence. The primary hypothesis 
involves testing the main effect for treatment difference between the groups (sham vs. active). A 
likelihood ratio test will examine the group effect focusing on the primary hypothesis. 
Secondary endpoint analyses are not powered, but may be used to demonstrate additional 
benefits of the treatment, provided it has been demonstrated that the primary endpoint shows clear 
statistical significance, as well as clinical meaningful benefits of the treatment [19]. Analysis of the 
secondary endpoint resembles primary endpoint analysis, using mixed-effect model testing for the 
between-group main effect.  
Given that participants can control the level of device stimulation, exploratory regression 
analyses will seek to identify potential relationships between device utilization (e.g. number of minutes 
device ‘on’ [non-zero intensity], average intensity while device ‘on’) and efficacy endpoints. 
Expected outcomes. We selected a single primary outcome (abstinence without MOUD). From 
our past experience at this same treatment facility, the expected group means for sham and NET arms 
are 0.48 and 3.97 weeks of average opioid abstinence with standard deviations 1.19 and 3.46, 
respectively. This results in effect size of 1.12. This effect size based on pilot data is rather large, 

 
 
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which is often the case due to limited scope of the pilot study. Thus, we took a conservative approach 
as suggested by Kraemer et al. [20] with moderate effect size of 0.45. 
Safety endpoints. Secondary safety endpoints (AEs, SAEs, ADEs, SADEs, UADEs and device 
deficiencies) will be summarized using descriptive statistics. 
Subgroup analysis. The analysis will stratify by sex (male/female) and non-opioid SUD 
(presence/absence). The expected outcome is that allocation on those variables will be balanced 
between the two groups. It is not anticipated that the primary outcome (opioid abstinence without 
MOUD) will differ across these subgroups. If significant baseline group imbalance is detected on any 
variable and its correlation with outcome (≥0.30), that variable will be included as a covariate in the 
inferential analyses. If systematic variation is noted by any subgroups for primary or secondary 
outcomes, further exploration will be conducted via cluster analysis. 
 
 
 

 
 
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Table 1. Example calculations of the primary efficacy endpoint measurement. 
 
Legend: 
1 = all drug tests and self-reports are negative 
h = illicit opioid (e.g., heroin) drug screen or self-report is positive 
m = medication for opioid use disorder (MOUD) or self-report is positive 
‘-‘ = missing value 
 
Cases measuring “abstinence without MOUD”: 
Heroin use, no MOUD 
{1,1,1,h,h,1,1,1,1,1,1,h}  
 
= 9/12 
Heroin use, no MOUD, missing weeks 
{1,1,1,h,h,1,-,-,1,1,-,-} 
 
= 6/12 
 
MOUD use, no Heroin 
{1,1,m,m,m,m,1,1,1,1,1,1}   
= 8/12 
MOUD use, no Heroin, missing weeks 
{1,1,m,m,m,m,1,1,-,-}  
 
= 4/12 
 
Heroin use, MOUD use 
{1,1,h,h,h+m,m,m,m,m,h,1,1}  
= 4/12  
Heroin use, MOUD use, missing weeks 
{1,1,h,h,h+m,m,-,-,m,h,-,-}   
= 2/12 
 
 

Table 2.  Participant selection criteria 
 
Inclusion Criteria 
Exclusion Criteria 
(1) Meet DSM-5 criteria for opioid use disorder (any 
severity level) alone or comorbid with stable medical 
diseases (except for certain medications below) 
(2) Stated desire to be opioid abstinent without 
medication for opioid use disorder 
(3) Initiating opioid discontinuation at study site 
(4) In good general health as evidenced by medical 
history 
(5) Male or female, aged 18-65 years 
(6) Provision of signed and dated informed consent and 
HIPAA authorization form 
(7) Stated willingness to comply with all study 
procedures and availability for the duration of the 
study (including inpatient stay and participation in 
video assessments and remote drug screens for the 
duration of the 12-week outpatient study period) 
(8) Use of highly effective contraception for at least 1 
month prior to screening and agreement to use such a 
method for the duration of the study 
(9) treatment will not commence until the Clinical Opiate 
Withdrawal Scale total score is 13 or greater (at least 
moderate withdrawal); thus, a consented participant 
could be dis-enrolled 
(1) Acute/unstable illness: conditions making it unsafe to 
participate 
(2) Chronic illnesses: primarily seizures and dementing illnesses, 
including medications for these neurological conditions 
(3) Current serious psychiatric disease: psychosis, bipolar disorder 
(4) Current requirement to detoxify for alcohol or benzodiazepines 
(5) Current use of anxiolytics, hypnotics (prescription and over-
the-counter), antidepressants, anticonvulsants, sedating H1 
antihistamines (non-sedating second generation H4 
antihistamines are allowed), prescription and over-the-counter 
stimulants 
(6) Current diagnosis other than opioid use disorder requiring 
chronic opioid treatment 
(7) Presence of a cardiac pacemaker 
(8) Pregnancy or lactation. Females who do not agree to sexual 
abstinence or are heterosexually active and not using (self-
report) medically approved birth control measures 
(sterilization, tubal ligation, oral/depot contraceptives, 
abstinence, intrauterine device, barrier method such as 
condom/foam, or a cervical cap combined with a spermicide), 
are not eligible 
(9) Receiving extended-release buprenorphine within 300 days of 
enrollment 
 
 
 
 

Figure 1. Upper panels: NET Device (left), mastoid-region electrode placement (middle), and cumulative distribution function of 
participants’ device utilization (percentage of sample with device “on”) across hours in two pilot studies conducted in Kentucky and 
Scotland (right). Lower panels: Time course of device intensity setting (left), and cumulative distribution functions of scores for the 
Subjective Opioid Withdrawal Scale (SOWS; middle) and craving (right). 
 
 
  
 

Figure 2. Study schema 
 
 
 
Notes: “NET”, NeuroElectric Therapy. “COWS”, Clinical Opiate Withdrawal Scale. “TLFB”, Timeline Followback.

Figure 3. Schedule of Activities 
 
Notes: “OP”, outpatient. “Wk”, week. “sa”, self-administered. “BP”, blood pressure. “COWS”, Clinical Opiate Withdrawal Scale, “HR”, heart rate. “RR”, 
respiration rate. “O2”, oxygen saturation.