Trial Outcomes & Findings for Trigeminal Nerve Stimulation for ADHD (NCT NCT02155608)

Last Updated: 2019-07-02

Results Overview

A dimensional rating of ADHD symptoms, with scores ranging from 0 - 54, and higher scores indicating greater symptom severity.

Recruitment status

COMPLETED

Study phase

Target enrollment

62 participants

Primary outcome timeframe

Change over baseline and weeks 1, 2, 3, 4 and 5.

Results posted on

2019-07-02

Participant Flow

Participants enrolled between 04/2015 and 03/2017. Participants were recruited through community advertisements and internet postings.

Potential participants underwent screening and those eligible returned for baseline assessment and randomization. Of 79 individuals screened, 64 met inclusion/exclusion criteria for participation. Two of these chose not to return after screening, most likely because they were only interested in ADHD assessment.

Participant milestones

Participant milestones
Measure	Active TNS Active TNS Active TNS: Participants randomized to active trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep.	Sham TNS Sham TNS Sham TNS: Participants randomized to sham trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep.
1a: 4 Week Double Blind Sham Controlled STARTED	32	30
1a: 4 Week Double Blind Sham Controlled COMPLETED	32	29
1a: 4 Week Double Blind Sham Controlled NOT COMPLETED	0	1
1b: 1 Week Blinded Post Treatment STARTED	32	29
1b: 1 Week Blinded Post Treatment COMPLETED	31	28
1b: 1 Week Blinded Post Treatment NOT COMPLETED	1	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Active TNS Active TNS Active TNS: Participants randomized to active trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep.	Sham TNS Sham TNS Sham TNS: Participants randomized to sham trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep.
1a: 4 Week Double Blind Sham Controlled Lost to Follow-up	0	1
1b: 1 Week Blinded Post Treatment Lost to Follow-up	1	1

Baseline Characteristics

Trigeminal Nerve Stimulation for ADHD

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Active eTNS n=32 Participants Following screening and determination of eligibility, participants at baseline are randomized to receive 4 weeks nightly treatment with active or sham eTNS, followed by one week ongoing blinded assessment following treatment discontinuation. Active eTNS: Participants will receive active trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep for 4 weeks, followed by one week of observation and followup while remaining blinded following treatment discontinuation. Participant deemed to be positive responders to blinded active treatment will be invited to continue open eTNS in a 12 month extension period.	Sham eTNS n=30 Participants Following screening and determination of eligibility, participants at baseline are randomized to receive 4 weeks nightly treatment with active or sham eTNS, followed by one week ongoing blinded assessment following treatment discontinuation. Sham eTNS: Participants will receive sham trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep for 4 weeks, followed by one week of observation and followup while remaining blinded following treatment discontinuation. At the conclusion of the blinded trial, participants randomized to the sham group will be offered 4 weeks of open eTNS treatment. Participants deemed to be positive responders to open treatment will be invited to continue open nightly eTNS in a 12 month extension period.	Total n=62 Participants Total of all reporting groups
Age, Continuous	10.26 years STANDARD_DEVIATION 1.39 • n=5 Participants	10.50 years STANDARD_DEVIATION 1.37 • n=7 Participants	10.40 years STANDARD_DEVIATION 1.4 • n=5 Participants
Sex: Female, Male Female	19 Participants n=5 Participants	21 Participants n=7 Participants	40 Participants n=5 Participants
Sex: Female, Male Male	13 Participants n=5 Participants	9 Participants n=7 Participants	22 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	5 Participants n=5 Participants	5 Participants n=7 Participants	10 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	27 Participants n=5 Participants	25 Participants n=7 Participants	52 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	5 Participants n=5 Participants	5 Participants n=7 Participants	10 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	4 Participants n=5 Participants	0 Participants n=7 Participants	4 Participants n=5 Participants
Race (NIH/OMB) White	20 Participants n=5 Participants	20 Participants n=7 Participants	40 Participants n=5 Participants
Race (NIH/OMB) More than one race	3 Participants n=5 Participants	5 Participants n=7 Participants	8 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
ADHD Subtype Combined	22 Participants n=5 Participants	17 Participants n=7 Participants	39 Participants n=5 Participants
ADHD Subtype Inattentive	9 Participants n=5 Participants	12 Participants n=7 Participants	21 Participants n=5 Participants
ADHD Subtype Hyperactive/Impulsive	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Full Scale IQ Estimate	110.4 IQ points STANDARD_DEVIATION 12.3 • n=5 Participants	107.3 IQ points STANDARD_DEVIATION 14.2 • n=7 Participants	108.9 IQ points STANDARD_DEVIATION 13.2 • n=5 Participants
ADHD-Rating Scale Total Score	32.13 units on a scale STANDARD_DEVIATION 6.28 • n=5 Participants	32.83 units on a scale STANDARD_DEVIATION 6.22 • n=7 Participants	32.47 units on a scale STANDARD_DEVIATION 6.21 • n=5 Participants
Clinical Global Impression - Severity 4 (Moderately iIl)	10 Participants n=5 Participants	11 Participants n=7 Participants	21 Participants n=5 Participants
Clinical Global Impression - Severity 5 (Markedly ill)	22 Participants n=5 Participants	19 Participants n=7 Participants	41 Participants n=5 Participants

PRIMARY outcome

Timeframe: Change over baseline and weeks 1, 2, 3, 4 and 5.

Population: Data missing for some visits.

A dimensional rating of ADHD symptoms, with scores ranging from 0 - 54, and higher scores indicating greater symptom severity.

Outcome measures

Outcome measures
Measure	Active eTNS n=32 Participants Following screening and determination of eligibility, participants at baseline are randomized to receive 4 weeks nightly treatment with active or sham eTNS, followed by one week ongoing blinded assessment following treatment discontinuation. Positive responders will be invited to participate in a 12-month open extension. Active eTNS: Participants will receive active trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep for 4 weeks, followed by one week of observation and followup while remaining blinded following treatment discontinuation. Participant deemed to be positive responders to blinded active treatment will be invited to continue open active eTNS in a 12 month extension period.	Sham eTNS n=30 Participants Following screening and determination of eligibility, participants at baseline are randomized to receive 4 weeks nightly treatment with active or sham eTNS, followed by one week ongoing blinded assessment following treatment discontinuation. Following double-blind phase, interested participants randomized to sham have an option for a 4-week open TNS trial. Positive responders will be invited to participate in a 12-month open extension. Sham eTNS: Participants will receive sham trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep for 4 weeks, followed by one week of observation and followup while remaining blinded following treatment discontinuation. At the conclusion of the blinded trial, participants randomized to the sham group will be offered 4 weeks of open eTNS treatment. Participants deemed to be positive responders to open treatment will be invited to continue open nightly active eTNS in a 12 month extension period.
ADHD-IV Rating Scale (ADHD-RS) Week 2	24.74 score on a scale Standard Error 1.40	28.31 score on a scale Standard Error 1.48
ADHD-IV Rating Scale (ADHD-RS) Week 3	23.92 score on a scale Standard Error 1.42	28.78 score on a scale Standard Error 1.50
ADHD-IV Rating Scale (ADHD-RS) Week 4	23.38 score on a scale Standard Error 1.40	27.50 score on a scale Standard Error 1.46
ADHD-IV Rating Scale (ADHD-RS) Baseline	32.12 score on a scale Standard Error 1.39	32.83 score on a scale Standard Error 1.43
ADHD-IV Rating Scale (ADHD-RS) Week 1	26.16 score on a scale Standard Error 1.39	28.53 score on a scale Standard Error 1.43
ADHD-IV Rating Scale (ADHD-RS) Week 5	25.5 score on a scale Standard Error 1.40	29.1 score on a scale Standard Error 1.47

SECONDARY outcome

Timeframe: Change over weeks 1, 2, 3, 4, and 5 compared with baseline.

Population: Data missing for some visits.

Categorical measure indicating degree improved or not improved compared with baseline for each treatment group. Minimum score = 1 (very much improved); Maximum score = 7 (very much worse). Results reflect number of participants stratified as "Improved" (CGI-I \<=2) or "Not Improved" (CGI-I \> 2).

Outcome measures

Outcome measures
Measure	Active eTNS n=32 Participants Following screening and determination of eligibility, participants at baseline are randomized to receive 4 weeks nightly treatment with active or sham eTNS, followed by one week ongoing blinded assessment following treatment discontinuation. Positive responders will be invited to participate in a 12-month open extension. Active eTNS: Participants will receive active trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep for 4 weeks, followed by one week of observation and followup while remaining blinded following treatment discontinuation. Participant deemed to be positive responders to blinded active treatment will be invited to continue open active eTNS in a 12 month extension period.	Sham eTNS n=30 Participants Following screening and determination of eligibility, participants at baseline are randomized to receive 4 weeks nightly treatment with active or sham eTNS, followed by one week ongoing blinded assessment following treatment discontinuation. Following double-blind phase, interested participants randomized to sham have an option for a 4-week open TNS trial. Positive responders will be invited to participate in a 12-month open extension. Sham eTNS: Participants will receive sham trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep for 4 weeks, followed by one week of observation and followup while remaining blinded following treatment discontinuation. At the conclusion of the blinded trial, participants randomized to the sham group will be offered 4 weeks of open eTNS treatment. Participants deemed to be positive responders to open treatment will be invited to continue open nightly active eTNS in a 12 month extension period.
Clinical Global Impression - Improvement (CGI-I) Week 2 · Improved	12 Participants	4 Participants
Clinical Global Impression - Improvement (CGI-I) Week 2 · Not Improved	19 Participants	22 Participants
Clinical Global Impression - Improvement (CGI-I) Week 4 · Not Improved	15 Participants	24 Participants
Clinical Global Impression - Improvement (CGI-I) Week 5 · Improved	4 Participants	2 Participants
Clinical Global Impression - Improvement (CGI-I) Week 1 · Improved	8 Participants	4 Participants
Clinical Global Impression - Improvement (CGI-I) Week 1 · Not Improved	24 Participants	26 Participants
Clinical Global Impression - Improvement (CGI-I) Week 3 · Improved	14 Participants	3 Participants
Clinical Global Impression - Improvement (CGI-I) Week 3 · Not Improved	16 Participants	22 Participants
Clinical Global Impression - Improvement (CGI-I) Week 4 · Improved	16 Participants	4 Participants
Clinical Global Impression - Improvement (CGI-I) Week 5 · Not Improved	27 Participants	26 Participants

SECONDARY outcome

Timeframe: Change over baseline and weeks 1, 2, 3, 4, 5.

Population: Data missing for some visits.

Parent completed dimensional measure of ADHD symptoms, with score range from 0- 30, and higher scores indicating more severe symptoms.

Outcome measures

Outcome measures
Measure	Active eTNS n=32 Participants Following screening and determination of eligibility, participants at baseline are randomized to receive 4 weeks nightly treatment with active or sham eTNS, followed by one week ongoing blinded assessment following treatment discontinuation. Positive responders will be invited to participate in a 12-month open extension. Active eTNS: Participants will receive active trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep for 4 weeks, followed by one week of observation and followup while remaining blinded following treatment discontinuation. Participant deemed to be positive responders to blinded active treatment will be invited to continue open active eTNS in a 12 month extension period.	Sham eTNS n=30 Participants Following screening and determination of eligibility, participants at baseline are randomized to receive 4 weeks nightly treatment with active or sham eTNS, followed by one week ongoing blinded assessment following treatment discontinuation. Following double-blind phase, interested participants randomized to sham have an option for a 4-week open TNS trial. Positive responders will be invited to participate in a 12-month open extension. Sham eTNS: Participants will receive sham trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep for 4 weeks, followed by one week of observation and followup while remaining blinded following treatment discontinuation. At the conclusion of the blinded trial, participants randomized to the sham group will be offered 4 weeks of open eTNS treatment. Participants deemed to be positive responders to open treatment will be invited to continue open nightly active eTNS in a 12 month extension period.
Conners Global Index - Parent Report Week 3	13.4 score on a scale Standard Error 1.1	15.2 score on a scale Standard Error 1.2
Conners Global Index - Parent Report Week 4	14.7 score on a scale Standard Error 14.7	14.6 score on a scale Standard Error 1.2
Conners Global Index - Parent Report Week 5	14.1 score on a scale Standard Error 1.1	15.7 score on a scale Standard Error 1.2
Conners Global Index - Parent Report Baseline	18.3 score on a scale Standard Error 1.1	17.4 score on a scale Standard Error 1.1
Conners Global Index - Parent Report Week 1	15.7 score on a scale Standard Error 1.1	16.5 score on a scale Standard Error 1.1
Conners Global Index - Parent Report Week 2	13.0 score on a scale Standard Error 1.1	15.2 score on a scale Standard Error 1.2

SECONDARY outcome

Timeframe: Change over baseline and weeks 4 and 5.

Population: Data missing for some visits

A child completed dimensional measure of emotional reactivity, with scores ranging from 0-12, and higher scores indicating greater severity.

Outcome measures

Outcome measures
Measure	Active eTNS n=32 Participants Following screening and determination of eligibility, participants at baseline are randomized to receive 4 weeks nightly treatment with active or sham eTNS, followed by one week ongoing blinded assessment following treatment discontinuation. Positive responders will be invited to participate in a 12-month open extension. Active eTNS: Participants will receive active trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep for 4 weeks, followed by one week of observation and followup while remaining blinded following treatment discontinuation. Participant deemed to be positive responders to blinded active treatment will be invited to continue open active eTNS in a 12 month extension period.	Sham eTNS n=30 Participants Following screening and determination of eligibility, participants at baseline are randomized to receive 4 weeks nightly treatment with active or sham eTNS, followed by one week ongoing blinded assessment following treatment discontinuation. Following double-blind phase, interested participants randomized to sham have an option for a 4-week open TNS trial. Positive responders will be invited to participate in a 12-month open extension. Sham eTNS: Participants will receive sham trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep for 4 weeks, followed by one week of observation and followup while remaining blinded following treatment discontinuation. At the conclusion of the blinded trial, participants randomized to the sham group will be offered 4 weeks of open eTNS treatment. Participants deemed to be positive responders to open treatment will be invited to continue open nightly active eTNS in a 12 month extension period.
Affective Reactivity Index (ARI) - Child Week 5	3.9 score on a scale Standard Error .5	3.5 score on a scale Standard Error .6
Affective Reactivity Index (ARI) - Child Baseline	4.5 score on a scale Standard Error .5	4.5 score on a scale Standard Error .5
Affective Reactivity Index (ARI) - Child Week 4	4.1 score on a scale Standard Error .5	3.8 score on a scale Standard Error .6

SECONDARY outcome

Timeframe: Change over baseline and weeks 4 and 5.

Population: Data missing for some visits.

A parent completed dimensional measure of emotional reactivity, with scores ranging from 0-12, and higher scores indicating greater severity.

Outcome measures

Outcome measures
Measure	Active eTNS n=32 Participants Following screening and determination of eligibility, participants at baseline are randomized to receive 4 weeks nightly treatment with active or sham eTNS, followed by one week ongoing blinded assessment following treatment discontinuation. Positive responders will be invited to participate in a 12-month open extension. Active eTNS: Participants will receive active trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep for 4 weeks, followed by one week of observation and followup while remaining blinded following treatment discontinuation. Participant deemed to be positive responders to blinded active treatment will be invited to continue open active eTNS in a 12 month extension period.	Sham eTNS n=30 Participants Following screening and determination of eligibility, participants at baseline are randomized to receive 4 weeks nightly treatment with active or sham eTNS, followed by one week ongoing blinded assessment following treatment discontinuation. Following double-blind phase, interested participants randomized to sham have an option for a 4-week open TNS trial. Positive responders will be invited to participate in a 12-month open extension. Sham eTNS: Participants will receive sham trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep for 4 weeks, followed by one week of observation and followup while remaining blinded following treatment discontinuation. At the conclusion of the blinded trial, participants randomized to the sham group will be offered 4 weeks of open eTNS treatment. Participants deemed to be positive responders to open treatment will be invited to continue open nightly active eTNS in a 12 month extension period.
Affective Reactivity Index (ARI) - Parent Report Baseline	4.4 score on a scale Standard Error .6	4.5 score on a scale Standard Error .6
Affective Reactivity Index (ARI) - Parent Report Week 4	3.6 score on a scale Standard Error .6	3.6 score on a scale Standard Error .7
Affective Reactivity Index (ARI) - Parent Report Week 5	3.8 score on a scale Standard Error .7	4.2 score on a scale Standard Error .7

SECONDARY outcome

Timeframe: Change over baseline and weeks 4 and 5.

Population: Data missing from some visits.

A child completed rating of child anxiety, with scores ranging from 0-300, and higher scores indicating greater severity.

Outcome measures

Outcome measures
Measure	Active eTNS n=32 Participants Following screening and determination of eligibility, participants at baseline are randomized to receive 4 weeks nightly treatment with active or sham eTNS, followed by one week ongoing blinded assessment following treatment discontinuation. Positive responders will be invited to participate in a 12-month open extension. Active eTNS: Participants will receive active trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep for 4 weeks, followed by one week of observation and followup while remaining blinded following treatment discontinuation. Participant deemed to be positive responders to blinded active treatment will be invited to continue open active eTNS in a 12 month extension period.	Sham eTNS n=30 Participants Following screening and determination of eligibility, participants at baseline are randomized to receive 4 weeks nightly treatment with active or sham eTNS, followed by one week ongoing blinded assessment following treatment discontinuation. Following double-blind phase, interested participants randomized to sham have an option for a 4-week open TNS trial. Positive responders will be invited to participate in a 12-month open extension. Sham eTNS: Participants will receive sham trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep for 4 weeks, followed by one week of observation and followup while remaining blinded following treatment discontinuation. At the conclusion of the blinded trial, participants randomized to the sham group will be offered 4 weeks of open eTNS treatment. Participants deemed to be positive responders to open treatment will be invited to continue open nightly active eTNS in a 12 month extension period.
Multidimensional Anxiety Scale for Children (MASC) - Child Report Baseline	61.0 score on a scale Standard Error 4.7	61.0 score on a scale Standard Error 4.9
Multidimensional Anxiety Scale for Children (MASC) - Child Report Week 4	59.5 score on a scale Standard Error 4.8	56.4 score on a scale Standard Error 4.7
Multidimensional Anxiety Scale for Children (MASC) - Child Report Week 5	56.1 score on a scale Standard Error 5.0	52.3 score on a scale Standard Error 5.3

SECONDARY outcome

Timeframe: Change over baseline and weeks 4 and 5.

Population: Data missing for some visits.

A parent completed rating of child anxiety, with scores ranging from 0-300, and higher scores indicating greater severity.

Outcome measures

Outcome measures
Measure	Active eTNS n=32 Participants Following screening and determination of eligibility, participants at baseline are randomized to receive 4 weeks nightly treatment with active or sham eTNS, followed by one week ongoing blinded assessment following treatment discontinuation. Positive responders will be invited to participate in a 12-month open extension. Active eTNS: Participants will receive active trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep for 4 weeks, followed by one week of observation and followup while remaining blinded following treatment discontinuation. Participant deemed to be positive responders to blinded active treatment will be invited to continue open active eTNS in a 12 month extension period.	Sham eTNS n=30 Participants Following screening and determination of eligibility, participants at baseline are randomized to receive 4 weeks nightly treatment with active or sham eTNS, followed by one week ongoing blinded assessment following treatment discontinuation. Following double-blind phase, interested participants randomized to sham have an option for a 4-week open TNS trial. Positive responders will be invited to participate in a 12-month open extension. Sham eTNS: Participants will receive sham trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep for 4 weeks, followed by one week of observation and followup while remaining blinded following treatment discontinuation. At the conclusion of the blinded trial, participants randomized to the sham group will be offered 4 weeks of open eTNS treatment. Participants deemed to be positive responders to open treatment will be invited to continue open nightly active eTNS in a 12 month extension period.
Multidimensional Anxiety Scale for Children (MASC) - Parent Report Baseline	46.2 score on a scale Standard Error 3.0	48.4 score on a scale Standard Error 3.1
Multidimensional Anxiety Scale for Children (MASC) - Parent Report Week 4	33.9 score on a scale Standard Error 3.0	42.9 score on a scale Standard Error 3.2
Multidimensional Anxiety Scale for Children (MASC) - Parent Report Week 5	32.4 score on a scale Standard Error 2.9	38.2 score on a scale Standard Error 3.0

SECONDARY outcome

Timeframe: Change over baseline and weeks 1, 4, and 5.

Population: Data missing for some visits.

A dimensional measure assessed in centimeters (cm).

Outcome measures

Outcome measures
Measure	Active eTNS n=32 Participants Following screening and determination of eligibility, participants at baseline are randomized to receive 4 weeks nightly treatment with active or sham eTNS, followed by one week ongoing blinded assessment following treatment discontinuation. Positive responders will be invited to participate in a 12-month open extension. Active eTNS: Participants will receive active trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep for 4 weeks, followed by one week of observation and followup while remaining blinded following treatment discontinuation. Participant deemed to be positive responders to blinded active treatment will be invited to continue open active eTNS in a 12 month extension period.	Sham eTNS n=30 Participants Following screening and determination of eligibility, participants at baseline are randomized to receive 4 weeks nightly treatment with active or sham eTNS, followed by one week ongoing blinded assessment following treatment discontinuation. Following double-blind phase, interested participants randomized to sham have an option for a 4-week open TNS trial. Positive responders will be invited to participate in a 12-month open extension. Sham eTNS: Participants will receive sham trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep for 4 weeks, followed by one week of observation and followup while remaining blinded following treatment discontinuation. At the conclusion of the blinded trial, participants randomized to the sham group will be offered 4 weeks of open eTNS treatment. Participants deemed to be positive responders to open treatment will be invited to continue open nightly active eTNS in a 12 month extension period.
Height Baseline	142.82 cm. Standard Error 1.78	141.45 cm. Standard Error 1.84
Height Week 1	142.79 cm. Standard Error 1.78	141.57 cm. Standard Error 1.84
Height Week 4	143.14 cm. Standard Error 1.78	142.31 cm. Standard Error 1.84
Height Week 5	143.58 cm. Standard Error 1.81	142.30 cm. Standard Error 1.90

SECONDARY outcome

Timeframe: Change over baseline and weeks 1, 4, and 5.

Population: Data missing for some visits.

A dimensional measure assessed in kilograms (kg).

Outcome measures

Outcome measures
Measure	Active eTNS n=32 Participants Following screening and determination of eligibility, participants at baseline are randomized to receive 4 weeks nightly treatment with active or sham eTNS, followed by one week ongoing blinded assessment following treatment discontinuation. Positive responders will be invited to participate in a 12-month open extension. Active eTNS: Participants will receive active trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep for 4 weeks, followed by one week of observation and followup while remaining blinded following treatment discontinuation. Participant deemed to be positive responders to blinded active treatment will be invited to continue open active eTNS in a 12 month extension period.	Sham eTNS n=30 Participants Following screening and determination of eligibility, participants at baseline are randomized to receive 4 weeks nightly treatment with active or sham eTNS, followed by one week ongoing blinded assessment following treatment discontinuation. Following double-blind phase, interested participants randomized to sham have an option for a 4-week open TNS trial. Positive responders will be invited to participate in a 12-month open extension. Sham eTNS: Participants will receive sham trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep for 4 weeks, followed by one week of observation and followup while remaining blinded following treatment discontinuation. At the conclusion of the blinded trial, participants randomized to the sham group will be offered 4 weeks of open eTNS treatment. Participants deemed to be positive responders to open treatment will be invited to continue open nightly active eTNS in a 12 month extension period.
Weight Baseline	38.83 kg. Standard Error 1.88	35.34 kg. Standard Error 1.95
Weight Week 1	39.12 kg. Standard Error 1.88	35.58 kg. Standard Error 1.95
Weight Week 4	39.65 kg. Standard Error 1.88	35.67 kg. Standard Error 1.95
Weight Week 5	39.85 kg. Standard Error 1.93	35.71 kg. Standard Error 2.03

SECONDARY outcome

Timeframe: Change over baseline and weeks 1, 4, and 5.

Population: Data missing from some visits.

A dimensional measure expressed in mm mercury (Hg).

Outcome measures

Outcome measures
Measure	Active eTNS n=32 Participants Following screening and determination of eligibility, participants at baseline are randomized to receive 4 weeks nightly treatment with active or sham eTNS, followed by one week ongoing blinded assessment following treatment discontinuation. Positive responders will be invited to participate in a 12-month open extension. Active eTNS: Participants will receive active trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep for 4 weeks, followed by one week of observation and followup while remaining blinded following treatment discontinuation. Participant deemed to be positive responders to blinded active treatment will be invited to continue open active eTNS in a 12 month extension period.	Sham eTNS n=30 Participants Following screening and determination of eligibility, participants at baseline are randomized to receive 4 weeks nightly treatment with active or sham eTNS, followed by one week ongoing blinded assessment following treatment discontinuation. Following double-blind phase, interested participants randomized to sham have an option for a 4-week open TNS trial. Positive responders will be invited to participate in a 12-month open extension. Sham eTNS: Participants will receive sham trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep for 4 weeks, followed by one week of observation and followup while remaining blinded following treatment discontinuation. At the conclusion of the blinded trial, participants randomized to the sham group will be offered 4 weeks of open eTNS treatment. Participants deemed to be positive responders to open treatment will be invited to continue open nightly active eTNS in a 12 month extension period.
Systolic Blood Pressure Baseline	108.50 mm Hg. Standard Error 2.26	106.10 mm Hg. Standard Error 2.36
Systolic Blood Pressure Week 1	107.03 mm Hg. Standard Error 2.26	109.20 mm Hg. Standard Error 2.34
Systolic Blood Pressure Week 4	111.00 mm Hg. Standard Error 2.26	107.79 mm Hg. Standard Error 2.36
Systolic Blood Pressure Week 5	112.26 mm Hg. Standard Error 2.02	106.10 mm Hg. Standard Error 2.13

SECONDARY outcome

Timeframe: Change over baseline and weeks 1, 4, and 5.

Population: Data missing for some visits.

A dimensional measure assessed in mm mercury (Hg).

Outcome measures

Outcome measures
Measure	Active eTNS n=32 Participants Following screening and determination of eligibility, participants at baseline are randomized to receive 4 weeks nightly treatment with active or sham eTNS, followed by one week ongoing blinded assessment following treatment discontinuation. Positive responders will be invited to participate in a 12-month open extension. Active eTNS: Participants will receive active trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep for 4 weeks, followed by one week of observation and followup while remaining blinded following treatment discontinuation. Participant deemed to be positive responders to blinded active treatment will be invited to continue open active eTNS in a 12 month extension period.	Sham eTNS n=30 Participants Following screening and determination of eligibility, participants at baseline are randomized to receive 4 weeks nightly treatment with active or sham eTNS, followed by one week ongoing blinded assessment following treatment discontinuation. Following double-blind phase, interested participants randomized to sham have an option for a 4-week open TNS trial. Positive responders will be invited to participate in a 12-month open extension. Sham eTNS: Participants will receive sham trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep for 4 weeks, followed by one week of observation and followup while remaining blinded following treatment discontinuation. At the conclusion of the blinded trial, participants randomized to the sham group will be offered 4 weeks of open eTNS treatment. Participants deemed to be positive responders to open treatment will be invited to continue open nightly active eTNS in a 12 month extension period.
Diastolic Blood Pressure Baseline	64.97 mm Hg. Standard Error 1.66	63.61 mm Hg. Standard Error 1.73
Diastolic Blood Pressure Week 1	63.69 mm Hg. Standard Error 1.66	62.33 mm Hg. Standard Error 1.71
Diastolic Blood Pressure Week 4	65.09 mm Hg. Standard Error 1.66	61.01 mm Hg. Standard Error 1.73
Diastolic Blood Pressure Week 5	65.30 mm Hg. Standard Error 1.76	60.89 mm Hg. Standard Error 1.86

SECONDARY outcome

Timeframe: Change over baseline and weeks weeks 1, 4, and 5.

Population: Data missing for some visits.

Heart rate in beats per minute (bpm).

Outcome measures

Outcome measures
Measure	Active eTNS n=32 Participants Following screening and determination of eligibility, participants at baseline are randomized to receive 4 weeks nightly treatment with active or sham eTNS, followed by one week ongoing blinded assessment following treatment discontinuation. Positive responders will be invited to participate in a 12-month open extension. Active eTNS: Participants will receive active trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep for 4 weeks, followed by one week of observation and followup while remaining blinded following treatment discontinuation. Participant deemed to be positive responders to blinded active treatment will be invited to continue open active eTNS in a 12 month extension period.	Sham eTNS n=30 Participants Following screening and determination of eligibility, participants at baseline are randomized to receive 4 weeks nightly treatment with active or sham eTNS, followed by one week ongoing blinded assessment following treatment discontinuation. Following double-blind phase, interested participants randomized to sham have an option for a 4-week open TNS trial. Positive responders will be invited to participate in a 12-month open extension. Sham eTNS: Participants will receive sham trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep for 4 weeks, followed by one week of observation and followup while remaining blinded following treatment discontinuation. At the conclusion of the blinded trial, participants randomized to the sham group will be offered 4 weeks of open eTNS treatment. Participants deemed to be positive responders to open treatment will be invited to continue open nightly active eTNS in a 12 month extension period.
Pulse Baseline	76.69 bpm. Standard Error 2.27	76.70 bpm. Standard Error 2.37
Pulse Week 1	79.91 bpm. Standard Error 2.27	79.70 bpm. Standard Error 2.34
Pulse Week 4	81.78 bpm. Standard Error 2.27	75.18 bpm. Standard Error 2.37
Pulse Week 5	79.42 bpm. Standard Error 2.10	78.18 bpm. Standard Error 2.22

SECONDARY outcome

Timeframe: Change over baseline and weeks 4 and 5.

Population: Data missing for some visits.

A child completed self-report dimensional measure of depressive symptoms, with range of scores from 0 to 54. Higher scores reflect increasing depression. Cutoff scores \< 17 to 20 are generally considered to be in the normative range. A score of 36 or higher reflects a relatively severe depression.

Outcome measures

Outcome measures
Measure	Active eTNS n=32 Participants Following screening and determination of eligibility, participants at baseline are randomized to receive 4 weeks nightly treatment with active or sham eTNS, followed by one week ongoing blinded assessment following treatment discontinuation. Positive responders will be invited to participate in a 12-month open extension. Active eTNS: Participants will receive active trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep for 4 weeks, followed by one week of observation and followup while remaining blinded following treatment discontinuation. Participant deemed to be positive responders to blinded active treatment will be invited to continue open active eTNS in a 12 month extension period.	Sham eTNS n=30 Participants Following screening and determination of eligibility, participants at baseline are randomized to receive 4 weeks nightly treatment with active or sham eTNS, followed by one week ongoing blinded assessment following treatment discontinuation. Following double-blind phase, interested participants randomized to sham have an option for a 4-week open TNS trial. Positive responders will be invited to participate in a 12-month open extension. Sham eTNS: Participants will receive sham trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep for 4 weeks, followed by one week of observation and followup while remaining blinded following treatment discontinuation. At the conclusion of the blinded trial, participants randomized to the sham group will be offered 4 weeks of open eTNS treatment. Participants deemed to be positive responders to open treatment will be invited to continue open nightly active eTNS in a 12 month extension period.
Children's Depression Inventory (CDI) Baseline	10.14 score on a scale Standard Error 1.23	9.10 score on a scale Standard Error 1.23
Children's Depression Inventory (CDI) Week 4	8.94 score on a scale Standard Error 1.22	8.21 score on a scale Standard Error 1.24
Children's Depression Inventory (CDI) Week 5	7.88 score on a scale Standard Error 1.32	7.34 score on a scale Standard Error 1.37

SECONDARY outcome

Timeframe: Change over baseline and weeks 1, 2, 3, 4, 5.

Population: Results may not be valid due to problems with data collection leading to substantial missing data.

Teacher completed dimensional measure of ADHD symptoms, with scores ranging from 0-30, and higher scores indicating more severe symptoms.

Outcome measures

Outcome measures
Measure	Active eTNS n=32 Participants Following screening and determination of eligibility, participants at baseline are randomized to receive 4 weeks nightly treatment with active or sham eTNS, followed by one week ongoing blinded assessment following treatment discontinuation. Positive responders will be invited to participate in a 12-month open extension. Active eTNS: Participants will receive active trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep for 4 weeks, followed by one week of observation and followup while remaining blinded following treatment discontinuation. Participant deemed to be positive responders to blinded active treatment will be invited to continue open active eTNS in a 12 month extension period.	Sham eTNS n=30 Participants Following screening and determination of eligibility, participants at baseline are randomized to receive 4 weeks nightly treatment with active or sham eTNS, followed by one week ongoing blinded assessment following treatment discontinuation. Following double-blind phase, interested participants randomized to sham have an option for a 4-week open TNS trial. Positive responders will be invited to participate in a 12-month open extension. Sham eTNS: Participants will receive sham trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep for 4 weeks, followed by one week of observation and followup while remaining blinded following treatment discontinuation. At the conclusion of the blinded trial, participants randomized to the sham group will be offered 4 weeks of open eTNS treatment. Participants deemed to be positive responders to open treatment will be invited to continue open nightly active eTNS in a 12 month extension period.
Conners Global Index - Teacher Baseline	15.76 score on a scale Standard Error 1.32	15.15 score on a scale Standard Error 1.32
Conners Global Index - Teacher Week 1	15.86 score on a scale Standard Error 1.23	11.37 score on a scale Standard Error 1.46
Conners Global Index - Teacher Week 2	14.36 score on a scale Standard Error 1.27	15.64 score on a scale Standard Error 1.77
Conners Global Index - Teacher Week 3	14.56 score on a scale Standard Error 1.92	16.56 score on a scale Standard Error 1.92
Conners Global Index - Teacher Week 4	15.43 score on a scale Standard Error 1.69	14.53 score on a scale Standard Error 1.89
Conners Global Index - Teacher Week 5	11.54 score on a scale Standard Error 3.33	18.83 score on a scale Standard Error 3.89

Adverse Events

Active TNS

Serious events: 0 serious events

Other events: 23 other events

Deaths: 0 deaths

Sham TNS

Serious events: 0 serious events

Other events: 22 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

James McGough, M.D.

University of California, Los Angeles

Phone: 310-794-7841

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Active TNS n=32 participants at risk Active TNS Active TNS: Participants randomized to active trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep.	Sham TNS n=30 participants at risk Sham TNS Sham TNS: Participants randomized to sham trigeminal nerve stimulation (TNS) administered by the Monarch eTNS System nightly during sleep.
Psychiatric disorders Trouble sleeping	18.8% 6/32 • Number of events 11 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.	16.7% 5/30 • Number of events 6 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.
Psychiatric disorders Nightmares	6.2% 2/32 • Number of events 2 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.	0.00% 0/30 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.
Nervous system disorders Drowsy	21.9% 7/32 • Number of events 9 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.	13.3% 4/30 • Number of events 5 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.
Psychiatric disorders Hyperactive	40.6% 13/32 • Number of events 27 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.	63.3% 19/30 • Number of events 40 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.
Psychiatric disorders Feels strange	0.00% 0/32 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.	6.7% 2/30 • Number of events 2 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.
Nervous system disorders Tingling	3.1% 1/32 • Number of events 1 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.	0.00% 0/30 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.
Nervous system disorders Headache	12.5% 4/32 • Number of events 4 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.	0.00% 0/30 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.
Respiratory, thoracic and mediastinal disorders Stuffy nose	15.6% 5/32 • Number of events 5 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.	20.0% 6/30 • Number of events 7 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.
Musculoskeletal and connective tissue disorders Muscle cramps	3.1% 1/32 • Number of events 1 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.	3.3% 1/30 • Number of events 1 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.
Nervous system disorders Tremor	0.00% 0/32 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.	3.3% 1/30 • Number of events 2 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.
Nervous system disorders Slurred speech	0.00% 0/32 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.	3.3% 1/30 • Number of events 1 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.
Cardiac disorders Rapid heartbeat	3.1% 1/32 • Number of events 1 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.	0.00% 0/30 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.
Respiratory, thoracic and mediastinal disorders Trouble catching breath	3.1% 1/32 • Number of events 1 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.	3.3% 1/30 • Number of events 1 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.
Gastrointestinal disorders Nausea	3.1% 1/32 • Number of events 1 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.	0.00% 0/30 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.
Gastrointestinal disorders Stomachache	6.2% 2/32 • Number of events 2 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.	3.3% 1/30 • Number of events 2 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.
Gastrointestinal disorders Constipation	9.4% 3/32 • Number of events 6 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.	10.0% 3/30 • Number of events 10 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.
Renal and urinary disorders Frequent urination	6.2% 2/32 • Number of events 5 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.	0.00% 0/30 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.
Nervous system disorders Frequent sweating	3.1% 1/32 • Number of events 1 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.	3.3% 1/30 • Number of events 1 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.
General disorders Decreased appetite	3.1% 1/32 • Number of events 1 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.	3.3% 1/30 • Number of events 1 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.
General disorders Increased appetite	18.8% 6/32 • Number of events 13 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.	6.7% 2/30 • Number of events 2 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.
Nervous system disorders Difficulty finding words	0.00% 0/32 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.	10.0% 3/30 • Number of events 6 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.
Skin and subcutaneous tissue disorders Skin rash	6.2% 2/32 • Number of events 2 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.	0.00% 0/30 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.
Psychiatric disorders Apathy	6.2% 2/32 • Number of events 2 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.	10.0% 3/30 • Number of events 3 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.
Psychiatric disorders Clenching teeth	12.5% 4/32 • Number of events 6 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.	10.0% 3/30 • Number of events 3 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.
General disorders Fatigue	12.5% 4/32 • Number of events 4 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.	3.3% 1/30 • Number of events 1 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.
Musculoskeletal and connective tissue disorders Muscle twitching	0.00% 0/32 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.	6.7% 2/30 • Number of events 3 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.
Psychiatric disorders Wish to be dead.	0.00% 0/32 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.	0.00% 0/30 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.
Psychiatric disorders Non-specific active suicidal thoughts	0.00% 0/32 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.	0.00% 0/30 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.
Psychiatric disorders Active suicidal ideation without intent	0.00% 0/32 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.	0.00% 0/30 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.
Psychiatric disorders Active suicidal ideation with some intent	0.00% 0/32 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.	0.00% 0/30 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.
Psychiatric disorders Active suicidal ideation with active plan and intent	0.00% 0/32 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.	0.00% 0/30 • Data were collected over the double-blind study, beginning at baseline and then weekly for 5 weeks. Adverse events were solicited via a structured side effects questionnaire and open inquiry completed at baseline and each weekly visit during the double-blind phases.