Trial Outcomes & Findings for Noninvasive Peripheral Nerve Stimulation for Restless Legs Syndrome During Opioid Medication Reduction (NCT NCT04698343)

Last Updated: 2024-09-19

Results Overview

Percentage of subjects without a clinically significant increase in RLS symptoms during the first Phase involving an opioid dose reduction of \>= 20% relative to baseline. The clinically significant increase was assessed by determining the Clinician Global Impression of Improvement (CGI-I) score for the subject. Possible choices (followed by scale value) are: Very much improved (1), Much improved (2), Minimally improved (3), No change (4), Minimally worse (5), Much worse (6), Very Much Worse (7). Scores of 6 or 7 would be considered a clinically significant increase in RLS Symptoms.

Recruitment status

COMPLETED

Study phase

Target enrollment

21 participants

Primary outcome timeframe

Week 1

Results posted on

2024-09-19

Participant Flow

20-40 planned, 21 enrolled, 20 analyzed \[1 enrolled in planned pilot phase, not part of analysis\]

Participants undergo an iterative opioid dose reduction alongside open-label NPNS administration. Each of the two dose step-downs (Phase 1 and Phase 2) involves a 1-2-wk run-in period followed by a 1-wk assessment. This ensures resolution of opioid withdrawal symptoms and confirms NPNS usage instructions. Study ends if RLS severity increases or not tolerated. Those tolerating both phases may opt for a third dose reduction extension.

Participant milestones

Participant milestones
Measure	Noninvasive Peripheral Nerve Stimulation (NPNS) NPNS device programmed to deliver active stimulation. Noninvasive Peripheral Nerve Stimulation (NPNS): NPNS device programmed to deliver active stimulation.
Overall Study STARTED	20
Overall Study Completed Phase 1	14
Overall Study Completed Phase 2	4
Overall Study Completed Phase 3	3
Overall Study COMPLETED	3
Overall Study NOT COMPLETED	17

Reasons for withdrawal

Reasons for withdrawal
Measure	Noninvasive Peripheral Nerve Stimulation (NPNS) NPNS device programmed to deliver active stimulation. Noninvasive Peripheral Nerve Stimulation (NPNS): NPNS device programmed to deliver active stimulation.
Overall Study Withdrawal by Subject	6
Overall Study Physician Decision	2
Overall Study Failed to meet the required reduction in opioid dosage due to increased RLS symptoms	4
Overall Study 1 was discontinued based on CGI-I score exceeding 5	1
Overall Study Personal reasons	3
Overall Study 1 withdrew due to non-RLS opioid withdrawal symptoms	1

Baseline Characteristics

Noninvasive Peripheral Nerve Stimulation for Restless Legs Syndrome During Opioid Medication Reduction

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Noninvasive Peripheral Nerve Stimulation (NPNS) n=20 Participants NPNS device programmed to deliver active stimulation. Noninvasive Peripheral Nerve Stimulation (NPNS): NPNS device programmed to deliver active stimulation.
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=5 Participants
Age, Continuous	62.9 years STANDARD_DEVIATION 10.2 • n=5 Participants
Sex: Female, Male Female	8 Participants n=5 Participants
Sex: Female, Male Male	12 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	18 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
IRLS total score at baseline, mean (SD)	9.8 units on a scale STANDARD_DEVIATION 8.5 • n=5 Participants
Duration of RLS symptoms, mean (SD), y	31.1 years STANDARD_DEVIATION 14.1 • n=5 Participants
Number of prior RLS medications, mean (SD)	3.2 number of RLS medications STANDARD_DEVIATION 1.6 • n=5 Participants
Prior RLS medications, n (%) - Dopamine agonist	19 Participants n=5 Participants
Prior RLS medications, n (%) - Alpha-2-delta ligand	12 Participants n=5 Participants
Prior RLS medications, n (%) - Benzodiazepine	4 Participants n=5 Participants
Prior RLS medications, n (%) - Opioid	2 Participants n=5 Participants
Duration of opioid treatment for RLS, mean (SD), years	8.0 years STANDARD_DEVIATION 4.6 • n=5 Participants
Baseline opioid dosage, mean (SD), Morphine Milligram Equivalents (MME)	39.0 MME STANDARD_DEVIATION 15.6 • n=5 Participants
Current RLS medications, n (%) - Methadone	18 Participants n=5 Participants
Current RLS medications, n (%) - Oxycodone	2 Participants n=5 Participants
Current RLS medications, n (%) - Dopamine agonist	4 Participants n=5 Participants
Current RLS medications, n (%) - Alpha-2-delta ligand	3 Participants n=5 Participants

PRIMARY outcome

Timeframe: Week 1

Population: All eligible subjects who passed screening and were enrolled in the study

Outcome measures

Outcome measures
Measure	Noninvasive Peripheral Nerve Stimulation (NPNS) n=20 Participants NPNS device programmed to deliver active stimulation. Noninvasive Peripheral Nerve Stimulation (NPNS): NPNS device programmed to deliver active stimulation.
Percentage of Subjects Without a Clinically Significant Increase in RLS Symptoms During the First Phase Involving an Opioid Dose Reduction of >= 20% Relative to Baseline.	14 Participants

SECONDARY outcome

Timeframe: 1 week

Percentage of subjects without a clinically significant increase in RLS symptoms during the first Phase involving an opioid dose reduction of \>= 1/3 relative to baseline. The clinically significant increase was assessed by determining the Clinician Global Impression of Improvement (CGI-I) score for the subject. Possible choices (followed by scale value) are: Very much improved (1), Much improved (2), Minimally improved (3), No change (4), Minimally worse (5), Much worse (6), Very Much Worse (7). Scores of 6 or 7 would be considered a clinically significant increase in RLS Symptoms.

Outcome measures

Outcome measures
Measure	Noninvasive Peripheral Nerve Stimulation (NPNS) n=14 Participants NPNS device programmed to deliver active stimulation. Noninvasive Peripheral Nerve Stimulation (NPNS): NPNS device programmed to deliver active stimulation.
Percentage of Subjects Without a Clinically Significant Increase in RLS Symptoms During the First Phase Involving an Opioid Dose Reduction of >= 1/3 Relative to Baseline.	8 Participants

SECONDARY outcome

Timeframe: 1 week

Population: These 19 subjects entered step-down #1, but 1 of the original 20 reduced their medication by 17% and so was not included in the analysis population for this secondary outcome.

IRLS is a participant-rated questionnaire that rates RLS severity from 0-40, where 40 is the most severe.

Outcome measures

Outcome measures
Measure	Noninvasive Peripheral Nerve Stimulation (NPNS) n=19 Participants NPNS device programmed to deliver active stimulation. Noninvasive Peripheral Nerve Stimulation (NPNS): NPNS device programmed to deliver active stimulation.
Change From Baseline in International Restless Legs Syndrome Study Group Rating Scale (IRLS) Score During Step-down #1 With an Opioid Dose Reduction of >=20%	5.8 units on a scale Standard Deviation 6.1

SECONDARY outcome

Timeframe: 1 week into Step-down #2

Population: The analysis population for this endpoint did not include the 3 subjects who were instructed to reduce opioid dose by \>= 1/3 but actually reduced opioid dose by \< 1/3 nor the 3 subjects who never were instructed to reduced opioid dose by \>= 1/3 due to dropout before that phase. Data were missing from one subject and Last Observation Carried Forward (LOCF) was used for imputation.

IRLS is a participant-rated questionnaire that rates RLS severity from 0-40, where 40 is the most severe.

Outcome measures

Outcome measures
Measure	Noninvasive Peripheral Nerve Stimulation (NPNS) n=14 Participants NPNS device programmed to deliver active stimulation. Noninvasive Peripheral Nerve Stimulation (NPNS): NPNS device programmed to deliver active stimulation.
Change From Baseline in International Restless Legs Syndrome Study Group Rating Scale (IRLS) Score During Step-down #2 With an Opioid Dose Reduction of >=1/3	5.7 units on a scale Standard Deviation 6.9

SECONDARY outcome

Timeframe: 1 week into final step-down

The clinically significant increase was assessed by determining the Clinician Global Impression of Improvement (CGI-I) score for the subject. Possible choices (followed by scale value) are: Very much improved (1), Much improved (2), Minimally improved (3), No change (4), Minimally worse (5), Much worse (6), Very Much Worse (7). Scores of 6 or 7 would be considered a clinically significant increase in RLS Symptoms.

Outcome measures

Outcome measures
Measure	Noninvasive Peripheral Nerve Stimulation (NPNS) n=20 Participants NPNS device programmed to deliver active stimulation. Noninvasive Peripheral Nerve Stimulation (NPNS): NPNS device programmed to deliver active stimulation.
Maximum Percent Change in Opioid Dose Relative to Baseline Without a Clinically Significant Increase in RLS Symptoms.	29.9 percent change Standard Deviation 23.7

OTHER_PRE_SPECIFIED outcome

Timeframe: Up to 9 weeks

Percentage of subjects who withdraw from study prior to the optional Phase 3 citing lack of tolerability of NPNS as the primary reason for withdrawal. The criterion for success was fewer than 20% of subjects who begin NPNS treatment withdrawing for this reason.

Outcome measures

Outcome measures
Measure	Noninvasive Peripheral Nerve Stimulation (NPNS) n=20 Participants NPNS device programmed to deliver active stimulation. Noninvasive Peripheral Nerve Stimulation (NPNS): NPNS device programmed to deliver active stimulation.
NPNS Tolerability Rate - Percentage of Subjects Who Withdrew From Optional Phase 3 Citing Lack of Tolerability of NPNS as the Primary Reason for Withdrawal.	0 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Up to 9 weeks

A Grade 2 adverse event is described as: moderate; minimal, local, or non-invasive intervention indicated; limiting age appropriate instrumental Activities of Daily Living such as preparing meals, shopping for groceries or clothes, using the telephone, and managing money. The success criteria was fewer than 20% Grade 2 or higher NPNS-related adverse events. (Definition from the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 NCI, NIH, US Department of Health and Human Services (DHHS). May 29, 2009 NIH publication #- 09-7473.)

Outcome measures

Outcome measures
Measure	Noninvasive Peripheral Nerve Stimulation (NPNS) n=20 Participants NPNS device programmed to deliver active stimulation. Noninvasive Peripheral Nerve Stimulation (NPNS): NPNS device programmed to deliver active stimulation.
Percentage of Grade 2 or Higher NPNS-related Adverse Events.	0 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Up to 9 weeks

The criteria for success were no Grade 3 or higher NPNS-related adverse events. A Grade 3 adverse event was described as: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care Activities of Daily Living such as bathing, dressing and undressing, feeding oneself, using the toilet, taking medications, and not being bedridden. (Definition from the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 NCI, NIH, DHHS. May 29, 2009 NIH publication #- 09-7473.)

Outcome measures

Outcome measures
Measure	Noninvasive Peripheral Nerve Stimulation (NPNS) n=20 Participants NPNS device programmed to deliver active stimulation. Noninvasive Peripheral Nerve Stimulation (NPNS): NPNS device programmed to deliver active stimulation.
Percentage of Grade 3 or Higher NPNS-related Adverse Events.	0 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 1 week post step-down

NPNS adherence was based on the percent of device usage on nights with RLS symptoms during Assessment periods. Adherence was assessed during assessment periods based on objective electronic records of completed device sessions. Subjects were instructed to complete a device session on all days with RLS symptoms. The global criterion for success percentage was \>=70%. The adherence ratio is the average days per week subjects completed device sessions divided by the average number of days that subjects experienced RLS symptoms.

Outcome measures

Outcome measures
Measure	Noninvasive Peripheral Nerve Stimulation (NPNS) n=14 Participants NPNS device programmed to deliver active stimulation. Noninvasive Peripheral Nerve Stimulation (NPNS): NPNS device programmed to deliver active stimulation.
NPNS Adherence Ratio During Step-down #1 and Step-down #2.	85 percentage of days per week with RLS Standard Deviation 24

Adverse Events

Noninvasive Peripheral Nerve Stimulation (NPNS)

Serious events: 0 serious events

Other events: 12 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Noninvasive Peripheral Nerve Stimulation (NPNS) n=20 participants at risk NPNS device programmed to deliver active stimulation. Noninvasive Peripheral Nerve Stimulation (NPNS): NPNS device programmed to deliver active stimulation.
General disorders Discomfort	45.0% 9/20 • Number of events 9 • Up to 9 weeks
Musculoskeletal and connective tissue disorders Restless Legs Syndrome	5.0% 1/20 • Number of events 1 • Up to 9 weeks
Skin and subcutaneous tissue disorders Skin irritation	10.0% 2/20 • Number of events 2 • Up to 9 weeks

Additional Information

Jonathan Charlesworth, PhD

Noctrix Health, Inc.

Phone: 804-683-4279

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place