Insomnia
Conditions
Keywords
Insomnia, Electroencephalic, Biofeedback, Neural oscillations, Auto calibration, Relaxation
Brief summary
The purpose of this study is to determine whether the addition of High-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM) to usual care will improve insomnia symptoms based on changes in the Insomnia Severity Index at two months following completion of the intervention, compared to placebo plus usual care.
Detailed description
Insomnia is the most prevalent sleep disorder and is associated with significant psychosocial and somatic pathology. Effective noninvasive interventions for insomnia are lacking. High-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM), is a noninvasive, brain feedback technology to facilitate relaxation and auto-calibration of neural oscillations by using auditory tones to reflect brain frequencies in near real time. An open label, randomized, crossover pilot trial showed that HIRREM was safe and effective, with significant benefits for individuals with moderate to severe insomnia, based on differential change with symptoms of insomnia (Insomnia Severity Index, ISI). This study will extend those results in a larger cohort using a single blind, placebo controlled study design.
Interventions
DEVICEHIRREM
Sponsors
Wake Forest University Health Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Moderate to severe clinical insomnia (Insomnia Severity Index score of 15 or higher)
Exclusion criteria
* Unable, unwilling, or incompetent to provide informed consent * Physically unable to come to the study visits * Known obstructive sleep apnea * Diagnosed periodic limb movement disorder or known restless legs syndrome * Known seizure disorder * Known urinary problem (i.e. benign prostatic hypertrophy) which is the likely cause of the sleep disturbance * Severe hearing impairment * Known, or suspected diagnosis of post-traumatic stress disorder (PTSD) * Known, relevant traumatic brain injury (TBI) * Ongoing need for treatment with opiate, benzodiazepine, or anti-psychotic medications, anti-depressant medications such as SSRI, SNRI, or tricyclics, and sleep medications such as zolpidem or eszopiclone * Anticipated and ongoing use of recreational drugs or alcohol * Lack of internet or smart phone access
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Insomnia Severity Index (ISI) | Collected from the enrollment visit through completion of the primary data collection visit, 8-10 weeks after completion of the intervention | The ISI is a 7 question, self-reported measure to evaluate symptoms of insomnia, with responses from 0-4 for each question, yielding scores ranging from 0-28. Lower scores represent better outcomes. The primary outcome will be change from enrollment to 8-10 weeks after completion of the intervention. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Total Sleep Time (TST) | Collected from the enrollment visit through completion of the primary data collection visit, 8-10 weeks after completion of the intervention | This will be an online daily sleep diary to evaluate the amount and quality of sleep. This allows evaluation of the timing and trajectory of any improvements in sleep, including appreciation of the presence and duration of placebo effects. Participants recorded the total sleep time (TST) they had each night. The outcome indicates the average increase (in hours) of the amount of sleep that each group reported. |
| Change in RestRefresh and SleepQual | Collected from the enrollment visit through completion of the primary data collection visit, 8-10 weeks after completion of the intervention | This will be an online daily sleep diary to evaluate the amount and quality of sleep. This allows evaluation of the timing and trajectory of any improvements in sleep, including appreciation of the presence and duration of placebo effects. Participants were asked to report a self-rating on how well they felt rested and refreshed (RestRefresh) and to rate the quality of sleep they had (SleepQual). Both questions were rated on a 0 to 4 scale and higher scores denotes better outcomes for each. |
| Change From Baseline in Beck Depression Inventory - II (BDI-II) | Collected from the enrollment visit through completion of the primary data collection visit, 8-10 weeks after completion of the intervention | Depression will be measured by the Beck Depression Inventory-II (BDI-II). The BDI-II is a 21-item questionnaire with response values of 0-3 for each item, yielding scores ranging from 0-63. Higher scores denotes worse outcomes. |
| Change From Baseline in Sleep Onset Latency and Wake After Sleep Onset | Baseline and 8-10 weeks after completion of intervention | This will be an online daily sleep diary to evaluate the amount and quality of sleep. This allows evaluation of the timing and trajectory of any improvements in sleep, including appreciation of the presence and duration of placebo effects. Measurements of sleep onset latency (SOL) and wake after sleep onset (WASO) were recorded in minutes. |
| Change From Baseline in EQ-5D | Collected from the enrollment visit through completion of the primary data collection visit, 8-10 weeks after completion of the intervention | Health-related quality of life will be measured by the EQ-5D. The EQ-5D consists of 5 items assessing an individual's current health status (values from 0-2), yielding scores ranging from 0-10. Higher scores denotes worse outcomes. |
| Change in Heart Rate Variability (HRV) | Collected from the enrollment visit through completion of the primary data collection visit, 8-10 weeks after completion of the intervention | Blood pressure and heart rate are acquired from 10 minute recordings of noninvasive finger arterial pressure measurements and ECG with participants lying quietly, supine. Systolic BP and beat to beat, RR intervals files generated via the data acquisition system (BIOPAC acquisition system and Acknowledge 4.2 software, Santa Barbara, CA), at 1000 Hz, are analyzed using Nevrokard BRS software (Nevrokard BRS, Medistar, Ljubljana, Slovenia). Analysis is conducted on the first complete 5-minute epoch that is considered to be acceptable for analysis. Heart rate variability is measured in the time domain as standard deviation of beat-to-beat interval (SDNN, milliseconds)and the root mean square of successive beat-to-beat differences in R-R interval duration (rMSSD milliseconds). For calculation of SDNN, the R-R intervals are visually inspected, and data considered as artifact is manually removed. |
| Change in Baroflex Sensitivity (BRS) | 8-10 weeks after completion of the intervention | Blood pressure and heart rate are acquired from 10 minute recordings of noninvasive finger arterial pressure measurements and ECG with participants lying quietly, supine. Systolic BP and beat to beat, RR intervals files generated via the data acquisition system at 1000 Hz, are analyzed using Nevrokard BRS software. Analysis is conducted on the first complete 5-minute epoch. Power spectral densities of systolic blood pressure (SBP) and R-R interval (RRI) oscillations are computed by 512 points Fast Fourier Transform (FFT) and integrated over specified frequency ranges (HF: 0.15-0.4 Hz). The square-root of the ratio of RRI's and SBP powers is computed to calculate HF alpha indices, which reflect BRS. The software scans the RRI and SBP records, identifies sequences, and calculates linear correlation between RRI and SBP for each sequence. The mean of all individual regression coefficients (slopes), a measure of sequence BRS, is then calculated for Sequence UP, DOWN and TOTAL (seq ALL). |
| Change From Baseline in Beck Anxiety Inventory (BAI) | Collected from the enrollment visit through completion of the primary data collection visit, 8-10 weeks after completion of the intervention | Anxiety will be measured by the Beck Anxiety Inventory (BAI). The BAI is a 21-item questionnaire with response values from 0-3 for each item, yielding scores ranging from 0-63. Higher scores denotes worse outcomes. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| HIRREM High-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM) is a novel, noninvasive, electroencephalic-based feedback technology to facilitate relaxation and auto-calibration of neural oscillations by using auditory tones to reflect brain frequencies in near real time.
HIRREM | 56 |
| Placebo Subjects in this arm will receive a sham-HIRREM placebo, for which the scalp sensors have no active recording capability, and for which the auditory tonal feedback is randomly generated rather than based on current brain frequencies and amplitudes.
HIRREM | 51 |
| Total | 107 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 2 |
Baseline characteristics
| Characteristic | HIRREM | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 52.4 years STANDARD_DEVIATION 15.1 | 54.7 years STANDARD_DEVIATION 14.8 | 53.5 years STANDARD_DEVIATION 14.9 |
| Duration with Sleep Trouble | 11.1 years STANDARD_DEVIATION 12.1 | 12.2 years STANDARD_DEVIATION 11.3 | 11.7 years STANDARD_DEVIATION 11.7 |
| Race/Ethnicity, Customized Ethnicity Other | 10 Participants | 8 Participants | 18 Participants |
| Race/Ethnicity, Customized Ethnicity White | 46 Participants | 43 Participants | 89 Participants |
| Sex: Female, Male Female | 41 Participants | 32 Participants | 73 Participants |
| Sex: Female, Male Male | 15 Participants | 19 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 56 | 0 / 51 |
| other Total, other adverse events | 6 / 56 | 7 / 51 |
| serious Total, serious adverse events | 0 / 56 | 0 / 51 |
Outcome results
Primary
Change From Baseline in Insomnia Severity Index (ISI)
The ISI is a 7 question, self-reported measure to evaluate symptoms of insomnia, with responses from 0-4 for each question, yielding scores ranging from 0-28. Lower scores represent better outcomes. The primary outcome will be change from enrollment to 8-10 weeks after completion of the intervention.
Time frame: Collected from the enrollment visit through completion of the primary data collection visit, 8-10 weeks after completion of the intervention
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HIRREM | Change From Baseline in Insomnia Severity Index (ISI) | -6.98 units on a scale | Standard Error 0.74 |
| Placebo | Change From Baseline in Insomnia Severity Index (ISI) | -4.94 units on a scale | Standard Error 0.76 |
Secondary
Change From Baseline in Beck Anxiety Inventory (BAI)
Anxiety will be measured by the Beck Anxiety Inventory (BAI). The BAI is a 21-item questionnaire with response values from 0-3 for each item, yielding scores ranging from 0-63. Higher scores denotes worse outcomes.
Time frame: Collected from the enrollment visit through completion of the primary data collection visit, 8-10 weeks after completion of the intervention
Population: Data not collected for one participant in the placebo group
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HIRREM | Change From Baseline in Beck Anxiety Inventory (BAI) | -0.25 units on a scale | Standard Error 0.1 |
| Placebo | Change From Baseline in Beck Anxiety Inventory (BAI) | -0.25 units on a scale | Standard Error 0.1 |
Secondary
Change From Baseline in Beck Depression Inventory - II (BDI-II)
Depression will be measured by the Beck Depression Inventory-II (BDI-II). The BDI-II is a 21-item questionnaire with response values of 0-3 for each item, yielding scores ranging from 0-63. Higher scores denotes worse outcomes.
Time frame: Collected from the enrollment visit through completion of the primary data collection visit, 8-10 weeks after completion of the intervention
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HIRREM | Change From Baseline in Beck Depression Inventory - II (BDI-II) | -3.76 units on a scale | Standard Error 0.59 |
| Placebo | Change From Baseline in Beck Depression Inventory - II (BDI-II) | -2.65 units on a scale | Standard Error 0.61 |
Secondary
Change From Baseline in EQ-5D
Health-related quality of life will be measured by the EQ-5D. The EQ-5D consists of 5 items assessing an individual's current health status (values from 0-2), yielding scores ranging from 0-10. Higher scores denotes worse outcomes.
Time frame: Collected from the enrollment visit through completion of the primary data collection visit, 8-10 weeks after completion of the intervention
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HIRREM | Change From Baseline in EQ-5D | 2.73 units on a scale | Standard Error 1.9 |
| Placebo | Change From Baseline in EQ-5D | 0.11 units on a scale | Standard Error 1.94 |
Secondary
Change From Baseline in Sleep Onset Latency and Wake After Sleep Onset
This will be an online daily sleep diary to evaluate the amount and quality of sleep. This allows evaluation of the timing and trajectory of any improvements in sleep, including appreciation of the presence and duration of placebo effects. Measurements of sleep onset latency (SOL) and wake after sleep onset (WASO) were recorded in minutes.
Time frame: Baseline and 8-10 weeks after completion of intervention
Population: Data was not able to be collected for all participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| HIRREM | Change From Baseline in Sleep Onset Latency and Wake After Sleep Onset | SOL | -1.00 minutes | Standard Error 0.18 |
| HIRREM | Change From Baseline in Sleep Onset Latency and Wake After Sleep Onset | WASO | -28.42 minutes | Standard Error 8 |
| Placebo | Change From Baseline in Sleep Onset Latency and Wake After Sleep Onset | SOL | -0.56 minutes | Standard Error 0.14 |
| Placebo | Change From Baseline in Sleep Onset Latency and Wake After Sleep Onset | WASO | -22.64 minutes | Standard Error 4.73 |
Secondary
Change in Baroflex Sensitivity (BRS)
Blood pressure and heart rate are acquired from 10 minute recordings of noninvasive finger arterial pressure measurements and ECG with participants lying quietly, supine. Systolic BP and beat to beat, RR intervals files generated via the data acquisition system at 1000 Hz, are analyzed using Nevrokard BRS software. Analysis is conducted on the first complete 5-minute epoch. Power spectral densities of systolic blood pressure (SBP) and R-R interval (RRI) oscillations are computed by 512 points Fast Fourier Transform (FFT) and integrated over specified frequency ranges (HF: 0.15-0.4 Hz). The square-root of the ratio of RRI's and SBP powers is computed to calculate HF alpha indices, which reflect BRS. The software scans the RRI and SBP records, identifies sequences, and calculates linear correlation between RRI and SBP for each sequence. The mean of all individual regression coefficients (slopes), a measure of sequence BRS, is then calculated for Sequence UP, DOWN and TOTAL (seq ALL).
Time frame: 8-10 weeks after completion of the intervention
Population: Other entries were excluded due to missing or dropped heartbeats and were excluded from the analysis for continuity
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| HIRREM | Change in Baroflex Sensitivity (BRS) | HF Alpha | 24.78 ms/mm Hg | Standard Error 2.17 |
| HIRREM | Change in Baroflex Sensitivity (BRS) | Seq ALL | 20.36 ms/mm Hg | Standard Error 2.03 |
| Placebo | Change in Baroflex Sensitivity (BRS) | HF Alpha | 16.26 ms/mm Hg | Standard Error 1.73 |
| Placebo | Change in Baroflex Sensitivity (BRS) | Seq ALL | 12.31 ms/mm Hg | Standard Error 1.09 |
Secondary
Change in Heart Rate Variability (HRV)
Blood pressure and heart rate are acquired from 10 minute recordings of noninvasive finger arterial pressure measurements and ECG with participants lying quietly, supine. Systolic BP and beat to beat, RR intervals files generated via the data acquisition system (BIOPAC acquisition system and Acknowledge 4.2 software, Santa Barbara, CA), at 1000 Hz, are analyzed using Nevrokard BRS software (Nevrokard BRS, Medistar, Ljubljana, Slovenia). Analysis is conducted on the first complete 5-minute epoch that is considered to be acceptable for analysis. Heart rate variability is measured in the time domain as standard deviation of beat-to-beat interval (SDNN, milliseconds)and the root mean square of successive beat-to-beat differences in R-R interval duration (rMSSD milliseconds). For calculation of SDNN, the R-R intervals are visually inspected, and data considered as artifact is manually removed.
Time frame: Collected from the enrollment visit through completion of the primary data collection visit, 8-10 weeks after completion of the intervention
Population: Other entries were excluded due to missing or dropped heartbeats and were excluded from the analysis for continuity
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| HIRREM | Change in Heart Rate Variability (HRV) | SDNN | 57.28 ms | Standard Error 1.34 |
| HIRREM | Change in Heart Rate Variability (HRV) | rMSSD | 53.06 ms | Standard Error 5.34 |
| Placebo | Change in Heart Rate Variability (HRV) | SDNN | 35.81 ms | Standard Error 1.77 |
| Placebo | Change in Heart Rate Variability (HRV) | rMSSD | 26.86 ms | Standard Error 2.24 |
Secondary
Change in RestRefresh and SleepQual
This will be an online daily sleep diary to evaluate the amount and quality of sleep. This allows evaluation of the timing and trajectory of any improvements in sleep, including appreciation of the presence and duration of placebo effects. Participants were asked to report a self-rating on how well they felt rested and refreshed (RestRefresh) and to rate the quality of sleep they had (SleepQual). Both questions were rated on a 0 to 4 scale and higher scores denotes better outcomes for each.
Time frame: Collected from the enrollment visit through completion of the primary data collection visit, 8-10 weeks after completion of the intervention
Population: Data was not able to be collected for all participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| HIRREM | Change in RestRefresh and SleepQual | RestRefresh | 0.60 units on a scale | Standard Error 0.16 |
| HIRREM | Change in RestRefresh and SleepQual | SleepQual | 0.79 units on a scale | Standard Error 0.16 |
| Placebo | Change in RestRefresh and SleepQual | RestRefresh | 0.54 units on a scale | Standard Error 0.12 |
| Placebo | Change in RestRefresh and SleepQual | SleepQual | 0.67 units on a scale | Standard Error 0.12 |
Secondary
Change in Total Sleep Time (TST)
This will be an online daily sleep diary to evaluate the amount and quality of sleep. This allows evaluation of the timing and trajectory of any improvements in sleep, including appreciation of the presence and duration of placebo effects. Participants recorded the total sleep time (TST) they had each night. The outcome indicates the average increase (in hours) of the amount of sleep that each group reported.
Time frame: Collected from the enrollment visit through completion of the primary data collection visit, 8-10 weeks after completion of the intervention
Population: Data was not able to be collected for all participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HIRREM | Change in Total Sleep Time (TST) | 1.15 hours | Standard Error 0.23 |
| Placebo | Change in Total Sleep Time (TST) | 0.58 hours | Standard Error 0.17 |