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| ID | Type | Description | Link |
|---|---|---|---|
| R44NS117294 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute of Neurological Disorders and Stroke (NINDS) | NIH |
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Prospective open-label single-arm feasibility study assessing the tolerability of opioid medication reduction in conjunction with noninvasive peripheral nerve stimulation (NPNS) for patients taking prescription opioids to treat moderate-severe primary RLS.
For RLS patients taking a stable dose of prescription opioid medications prior to study entry, iterative opioid dose reduction is performed in conjunction with open-label NPNS treatment. For each of two iterative step-downs in opioid dose (step-down #1 and step-down #2), a 1-2-week run-in phase to allow resolution of opioid withdrawal symptoms unrelated to RLS is followed by a 1-wk assessment phase to evaluate if RLS symptoms have increased. Study participation is terminated if there is a clinically significant increase in RLS severity during the assessment phase or if there are intolerable opioid withdrawal symptoms at any time. Participants who tolerate both step-downs have the option of an extension phase involving a third step-down with the same format.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Noninvasive Peripheral Nerve Stimulation (NPNS) | Experimental | NPNS device programmed to deliver active stimulation. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Noninvasive Peripheral Nerve Stimulation (NPNS) | Device | NPNS device programmed to deliver active stimulation. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 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. | Week 1 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| NPNS Tolerability Rate - Percentage of Subjects Who Withdrew From Optional Phase 3 Citing Lack of Tolerability of NPNS as the Primary Reason for Withdrawal. | 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. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jonathan D Charlesworth, PhD | Noctrix Health, Inc. | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Mark J Buchfuhrer private practice | Downey | California | 90241 | United States | ||
| Ohio Sleep Medicine Institute |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37990163 | Derived | Buchfuhrer MJ, Roy A, Rodriguez S, Charlesworth JD. Adjunctive tonic motor activation enables opioid reduction for refractory restless legs syndrome: a prospective, open-label, single-arm clinical trial. BMC Neurol. 2023 Nov 21;23(1):415. doi: 10.1186/s12883-023-03462-6. |
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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.
20-40 planned, 21 enrolled, 20 analyzed
[1 enrolled in planned pilot phase, not part of analysis]
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| ID | Title | Description |
|---|---|---|
| FG000 | Noninvasive Peripheral Nerve Stimulation (NPNS) | NPNS device programmed to deliver active stimulation. Noninvasive Peripheral Nerve Stimulation (NPNS): NPNS device programmed to deliver active stimulation. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Noninvasive Peripheral Nerve Stimulation (NPNS) | NPNS device programmed to deliver active stimulation. Noninvasive Peripheral Nerve Stimulation (NPNS): NPNS device programmed to deliver active stimulation. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | 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. | All eligible subjects who passed screening and were enrolled in the study | Posted | Count of Participants | Participants | Week 1 |
|
Up to 9 weeks
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Noninvasive Peripheral Nerve Stimulation (NPNS) | NPNS device programmed to deliver active stimulation. Noninvasive Peripheral Nerve Stimulation (NPNS): NPNS device programmed to deliver active stimulation. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Discomfort | General disorders | MedDRA (Unspecified) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Jonathan Charlesworth, PhD | Noctrix Health, Inc. | 804-683-4279 | jcharlesworth@noctrixhealth.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Sep 24, 2021 | Mar 21, 2024 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Jul 23, 2021 | May 22, 2024 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D012148 | Restless Legs Syndrome |
| ID | Term |
|---|---|
| D009422 | Nervous System Diseases |
| D020919 | Sleep Disorders, Intrinsic |
| D020920 | Dyssomnias |
| D012893 | Sleep Wake Disorders |
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| 1 week |
| 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% | IRLS is a participant-rated questionnaire that rates RLS severity from 0-40, where 40 is the most severe. | 1 week |
| 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 | IRLS is a participant-rated questionnaire that rates RLS severity from 0-40, where 40 is the most severe. | 1 week into Step-down #2 |
| Maximum Percent Change in Opioid Dose Relative to Baseline Without a Clinically Significant Increase in RLS Symptoms. | 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. | 1 week into final step-down |
| Up to 9 weeks |
| Percentage of Grade 2 or Higher NPNS-related Adverse Events. | 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.) | Up to 9 weeks |
| Percentage of Grade 3 or Higher NPNS-related Adverse Events. | 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.) | Up to 9 weeks |
| NPNS Adherence Ratio During Step-down #1 and Step-down #2. | 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. | 1 week post step-down |
| Dublin |
| Ohio |
| 43017 |
| United States |
| 1 was discontinued based on CGI-I score exceeding 5 |
|
| Personal reasons |
|
| 1 withdrew due to non-RLS opioid withdrawal symptoms |
|
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| IRLS total score at baseline, mean (SD) | Mean | Standard Deviation | units on a scale |
|
| Duration of RLS symptoms, mean (SD), y | Mean | Standard Deviation | years |
|
| Number of prior RLS medications, mean (SD) | Mean | Standard Deviation | number of RLS medications |
|
| Prior RLS medications, n (%) - Dopamine agonist | Count of Participants | Participants |
|
| Prior RLS medications, n (%) - Alpha-2-delta ligand | Count of Participants | Participants |
|
| Prior RLS medications, n (%) - Benzodiazepine | Count of Participants | Participants |
|
| Prior RLS medications, n (%) - Opioid | Count of Participants | Participants |
|
| Duration of opioid treatment for RLS, mean (SD), years | Mean | Standard Deviation | years |
|
| Baseline opioid dosage, mean (SD), Morphine Milligram Equivalents (MME) | Mean | Standard Deviation | MME |
|
| Current RLS medications, n (%) - Methadone | Count of Participants | Participants |
|
| Current RLS medications, n (%) - Oxycodone | Count of Participants | Participants |
|
| Current RLS medications, n (%) - Dopamine agonist | Count of Participants | Participants |
|
| Current RLS medications, n (%) - Alpha-2-delta ligand | Count of Participants | Participants |
|
NPNS device programmed to deliver active stimulation. Noninvasive Peripheral Nerve Stimulation (NPNS): NPNS device programmed to deliver active stimulation. |
|
|
| Secondary | 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. | 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. | Posted | Count of Participants | Participants | 1 week |
|
|
|
| Secondary | 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% | IRLS is a participant-rated questionnaire that rates RLS severity from 0-40, where 40 is the most severe. | 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. | Posted | Mean | Standard Deviation | units on a scale | 1 week |
|
|
|
| Secondary | 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 | IRLS is a participant-rated questionnaire that rates RLS severity from 0-40, where 40 is the most severe. | 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. | Posted | Mean | Standard Deviation | units on a scale | 1 week into Step-down #2 |
|
|
|
| Secondary | Maximum Percent Change in Opioid Dose Relative to Baseline Without a Clinically Significant Increase in RLS Symptoms. | 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. | Posted | Mean | Standard Deviation | percent change | 1 week into final step-down |
|
|
|
| Other Pre-specified | NPNS Tolerability Rate - Percentage of Subjects Who Withdrew From Optional Phase 3 Citing Lack of Tolerability of NPNS as the Primary Reason for Withdrawal. | 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. | Posted | Count of Participants | Participants | Up to 9 weeks |
|
|
|
| Other Pre-specified | Percentage of Grade 2 or Higher NPNS-related Adverse Events. | 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.) | Posted | Count of Participants | Participants | Up to 9 weeks |
|
|
|
| Other Pre-specified | Percentage of Grade 3 or Higher NPNS-related Adverse Events. | 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.) | Posted | Count of Participants | Participants | Up to 9 weeks |
|
|
|
| Other Pre-specified | NPNS Adherence Ratio During Step-down #1 and Step-down #2. | 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. | Posted | Mean | Standard Deviation | percentage of days per week with RLS | 1 week post step-down |
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|
|
| 0 |
| 20 |
| 0 |
| 20 |
| 12 |
| 20 |
| Restless Legs Syndrome | Musculoskeletal and connective tissue disorders | MedDRA (Unspecified) | Systematic Assessment | Increased RLS symptoms due to Reduction in medication. |
|
| Skin irritation | Skin and subcutaneous tissue disorders | MedDRA (Unspecified) | Systematic Assessment |
|
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| D020447 |
| Parasomnias |
| D001523 | Mental Disorders |