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HIRREM in Military Personnel

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ClinicalTrials.gov Identifier: NCT03230890
Recruitment Status : Recruiting
First Posted : July 27, 2017
Last Update Posted : November 7, 2018
Sponsor:
Collaborator:
Brain State Technologies, LLC
Information provided by (Responsible Party):
Wake Forest University Health Sciences

Brief Summary:
The purpose of this study is to evaluate the effects associated with the use of in-office High-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM) for participants with symptoms of military-related traumatic stress. This is a single site, non-randomized, open label pilot study. Outcome measures collected before, and after the intervention evaluate effects on self-reported symptoms, autonomic cardiovascular regulation, functional measures, blood and saliva biomarkers of stress and inflammation, and network connectivity on whole brain, rest MRI testing. Self-reported symptom outcomes will also be collected remotely at 1, 3, and 6 months after completion of intervention. The study will assess feasibility in this cohort, focused on the Special Operations community, will provide estimates of effect size, and durability of symptom changes, while providing important pilot data for future proposals and investigations.

Condition or disease Intervention/treatment Phase
Stress Disorders, Post-Traumatic Device: HIRREM Not Applicable

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Intervention Model: Single Group Assignment
Intervention Model Description: Single site, non-randomized, single arm, open label design,with collection of outcome measures before, and at intervals after the intervention
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: HIRREM for Mitigation of PTSD Symptoms in Military Personnel
Actual Study Start Date : February 16, 2015
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : June 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: HIRREM
This is the intervention, treatment arm that all participants receive in this open label, single arm trial. The intervention is High-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM).
Device: HIRREM
HIRREM is a closed-loop, allostatic, acoustic stimulation neurotechnology intended to support auto-calibration of neural oscillations. The core technology is commercially available as a technique for relaxation. Scalp sensors monitor brain frequencies and amplitudes, and in real time, software algorithms translate specific frequencies into audible tones of varying pitch. These are reflected via earbuds in as little as 4-8 milliseconds. The in-office intervention for this study is administered as a series of up to twenty four, typically 1.5-2 hours sessions, comprised of 4-10 protocols (some eyes open, some eyes closed), lasting 6-40 minutes each, working at different scalp locations. Sessions are received over 12 days. Two sessions can be done in a half day. The intervention is received while comfortably seated in a zero gravity chair.




Primary Outcome Measures :
  1. PCL-M [ Time Frame: Data for the primary symptom outcome is collected at enrollment, and immediately following completion of the HIRREM intervention. ]
    The PTSD Checklist (PCL) - Civilian (C) and Military (M) is a symptom checklist to measure stress severity due to a traumatic experience, in civilian or military settings, respectively. The PCL measures the American Psychiatric Association's Diagnostic and statistical manual of mental disorders (DSM-IV) Criteria B, C, & D of PTSD symptoms based on traumatic life experience. Seventeen items are rated on a Likert scale with a composite score range of 17 to 85. Primary outcome for this pilot study will be change in PCL-M score from baseline to the immediate post-intervention in-person data collection at the completion of the HIRREM intervention. Outcomes with the PCL-M will also be collected remotely at 1, 3, and 6 months following completion of the intervention.


Secondary Outcome Measures :
  1. PCL-M [ Time Frame: PCL-M data collected at enrollment, and at 1, 3, and 6 months post-intervention will be analyzed as a secondary outcome. ]
    The PTSD Checklist (PCL) - Civilian (C) and Military (M) is a symptom checklist to measure stress severity due to a traumatic experience, in civilian or military settings, respectively. The PCL measures the American Psychiatric Association's Diagnostic and statistical manual of mental disorders (DSM-IV) Criteria B, C, & D of PTSD symptoms based on traumatic life experience. Seventeen items are rated on a Likert scale with a composite score range of 17 to 85. Change in the PCL-M score from baseline to immediate post-intervention is the primary outcome. However, PCL-M scores will also be collected remotely at 1, 3, and 6 months following completion of the intervention to assess durability of effect. These later data collections will be considered secondary outcomes.

  2. Center for Epidemiologic Studies Depression Scale (CES-D) [ Time Frame: Data for secondary symptom outcomes is collected at enrollment, immediately following completion of the intervention, and at later remote data collections 1, 3, and 6 months post-intervention. ]
    The CES-D is a 20-item survey assessing affective depressive symptomatology to screen for risk of depression. Scores range from 0-60, with a score of 16 commonly used as a clinically relevant cut-off. Secondary outcome with the CES-D will be analyzed for change from baseline to the immediate post-HIRREM in person data collection, as well as remote data collections 1, 3, and 6 months post-intervention.

  3. Insomnia Severity Index (ISI) [ Time Frame: Data for secondary symptom outcomes is collected at enrollment, immediately following completion of the intervention, and at later remote data collections 1, 3, and 6 months post-intervention. ]
    The severity of insomnia symptoms is measured using the ISI with each data collection visit. The ISI is a 7 question measure, with responses from 0-4 for each question, yielding scores ranging from 0-28. Secondary outcome with the ISI will be analyzed for change from baseline to the immediate post-HIRREM in person data collection, as well as remote data collections 1, 3, and 6 months post-intervention.

  4. Generalized Anxiety Disorder-7 (GAD-7) [ Time Frame: Data for secondary symptom outcomes is collected at enrollment, immediately following completion of the intervention, and at later remote data collections 1, 3, and 6 months post-intervention. ]
    The Generalized Anxiety Disorder-7 (GAD-7) is a seven item screening tool for anxiety that is widely used in primary care. Secondary outcome with the GAD-7 will be analyzed for change from baseline to the immediate post-HIRREM in person data collection, as well as remote data collections 1, 3, and 6 months post-intervention.

  5. Rivermead Post-Concussion Symptoms Questionnaire (RPQ) [ Time Frame: Data for secondary symptom outcomes is collected at enrollment, immediately following completion of the intervention, and at later remote data collections 1, 3, and 6 months post-intervention. ]
    The Rivermead Post-Concussion Symptoms Questionnaire (RPQ) is a 16-item survey that assesses the severity of the most common post-concussion symptoms on a scale of 0 to 4, with a total score range from 0 to 64 (least to greatest symptom severity). Items are compared to levels before the head injury and are reported as a 24 hour recall. Secondary outcome with the RPQ will be analyzed for change from baseline to the immediate post-HIRREM in person data collection, as well as remote data collections 1, 3, and 6 months post-intervention.

  6. EQ-5D [ Time Frame: Data for secondary symptom outcomes is collected at enrollment, immediately following completion of the intervention, and at later remote data collections 1, 3, and 6 months post-intervention. ]
    The EQ-5D is a brief, standardized measure of health status developed by the EuroQol Group, and is a paper and pencil survey providing a single index value for health status. Secondary outcome with the EQ-5D will be analyzed for change from baseline to the immediate post-HIRREM in person data collection, as well as remote data collections 1, 3, and 6 months post-intervention.

  7. Heart rate variability [ Time Frame: Data for secondary autonomic outcomes is collected at enrollment, and immediately following completion of the intervention. ]
    Secondary autonomic outcome with heart rate variability will be analyzed for change from baseline to the immediate post-HIRREM in person data collection.

  8. Baroreflex Sensitivity HF alpha [ Time Frame: Data for secondary autonomic outcomes is collected at enrollment, and immediately following 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 Baroreflex Sensitivity (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. Evaluation includes analysis for measures of spontaneous baroreflex sensitivity (BRS), in the frequency domain as high frequency (HF) alpha index (ms2). Secondary autonomic outcome with BRS will be analyzed for change from baseline to the immediate post-HIRREM in person data collection.

  9. Baroreflex Sensitivity Sequence Up [ Time Frame: Data for secondary autonomic outcomes is collected at enrollment, and immediately following 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 Baroreflex Sensitivity (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. Evaluation includes analysis for measures of spontaneous baroreflex sensitivity (BRS), in the time domain as frequency domain as BRS Sequence Up (ms/mmHg). Secondary autonomic outcome with BRS will be analyzed for change from baseline to the immediate post-HIRREM in person data collection.

  10. Baroreflex Sensitivity Sequence Down [ Time Frame: Data for secondary autonomic outcomes is collected at enrollment, and immediately following 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 Baroreflex Sensitivity (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. Evaluation includes analysis for measures of spontaneous baroreflex sensitivity (BRS), in the time domain as frequency domain as BRS Sequence Down (ms/mmHg). Secondary autonomic outcome with BRS will be analyzed for change from baseline to the immediate post-HIRREM in person data collection.

  11. Baroreflex Sensitivity Sequence All [ Time Frame: Data for secondary autonomic outcomes is collected at enrollment, and immediately following 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 Baroreflex Sensitivity (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. Evaluation includes analysis for measures of spontaneous baroreflex sensitivity (BRS), in the time domain as frequency domain as BRS Sequence All (ms/mmHg). Secondary autonomic outcome with BRS will be analyzed for change from baseline to the immediate post-HIRREM in person data collection.

  12. Drop stick reaction time [ Time Frame: Data for secondary functional outcomes is collected at enrollment, and immediately following completion of the intervention. ]
    Reaction testing is measured by a drop-stick apparatus that has been validated as a way to quantify the impact of athletic concussion on psychomotor performance. Following two practice trials, participants perform eight trials, and a mean distance value is calculated. Secondary functional outcome with drop-stick reaction time will be analyzed for changes in distance from baseline to the in person data collection immediately after completion of the intervention.

  13. Grip Strength [ Time Frame: Data for secondary functional outcomes is collected at enrollment, and immediately following completion of the intervention. ]
    Grip strength will evaluated using a hydraulic hand dynamometer (Baseline Hydraulic Hand Dynamometer). Both right and left hand will be evaluated, and the greatest force generated during three trials will be used for analysis

  14. Functional MRI [ Time Frame: MRI scans will be obtained at enrollment, and immediately after completion of the intervention. ]
    Anatomical and physiological brain imaging will be performed during a 1-hour imaging session at baseline and immediately following completion of the intervention. This will include imaging sequences such as high resolution structural scans. Brain network data will be collected using blood oxygenation level dependent (BOLD) scans. These scans will be collected under various states such as at rest. All images will be acquired using a 3 Tesla Siemens MRI scanner. Whole-brain network connectivity will be assessed using blood oxygenation level dependent (BOLD) imaging. Community structure will be determined for each participant pre- and post-intervention. This project will specifically focus on the community including the Default Mode Network (DMN). For each participant the strength of the community structure will be determined of the DMN. Permutation analysis will be used to evaluate for significant pattern change in specific networks, from baseline to post-intervention.

  15. Blood biomarkers for stress and inflammation [ Time Frame: Blood biomarkers for stress and inflammation will be obtained at enrollment, and at completion of the intervention. ]
    Blood for a panel of biomarkers for stress will be collected at enrollment, and after completion of the intervention. The panel includes Ang II, Ang 1-7, Epinephrine, Norepinephrine, C-reactive protein, Vasopressin, IL-1, IL-6, and IL-10.

  16. Salivary biomarkers for stress [ Time Frame: Salivary biomarkers for stress will be obtained at enrollment, and at completion of the intervention. ]
    Saliva for a panel of salivary biomarkers for stress will be collected at enrollment, and after completion of the intervention. The panel includes salivary cortisol, and alpha-amylase.

  17. Epigenetic markers [ Time Frame: Blood for epigenetic markers is obtained at enrollment, and at completion of the intervention. ]
    DNA will be isolated from whole blood, collected in yellow-top Vacutainer tubes (ACD as the preservative), using the AutoPure LS system in the Genomics Center Core lab. DNA will be bisulfite-converted using the EZ DNA Methylation Gold kit (Zymo, Irvine, CA). To quantify DNA methylation at each site, investigators will use the HumanMethylation450 BeadChip (Illumina, Inc.), which targets over 485,000 CpG sites at single-nucleotide resolution, and the HiScan Reader (Illumina, Inc.). This microarray assays CpG sites from 99% of the RefSeq genes, with an average of 17 CpG sites per gene region distributed across the promoter, 5'UTR, first exon, gene body, and 3'UTR. The methylation proportion for each site (beta value) is based on the ratio of the fluorescence intensity of the methylated versus the combined methylated and unmethylated probes, and will be determined with GenomeStudio (Illumina, Inc.). A ratio of 0 equals no methylation and a ratio of 1 equals total (100%) methylation.

  18. Sleep diary [ Time Frame: Sleep diary data will be collected daily via online access from the enrollment visit through one month post-intervention. ]
    An online daily sleep diary will be maintained from enrollment, through the one month post-intervention remote data collection.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Active duty military personnel, or recent veterans (Operation Enduring Freedom, Operation Iraqi Freedom, or Operation New Dawn), men and women, with a diagnosis of PTSD, or active symptoms suggesting PTSD as identified by a screening PCL-M score of 50 or greater, with or without traumatic brain injury (TBI), are eligible to participate in the study.

Exclusion Criteria:

  • Unable, unwilling, or incompetent to provide informed consent
  • Physically unable to come to the study visits, or to sit in a chair for several hours
  • Known seizure disorder
  • Severe hearing impairment (because the subject will be using ear buds during HIRREM)
  • Ongoing need for treatment with opiate, benzodiazepine, or anti-psychotic medications, anti-depressant medications (SSRI, or SNRI's), sleep medications such as zolpidem or eszopiclone, stimulants such as Adderall, Provigil, or Ritalin, or thyroid hormone
  • Anticipated and ongoing use of recreational drugs, alcohol, or energy drinks
  • Lack of internet or smart phone access (will maintain remote access daily sleep diary through 1 month post-HIRREM visit)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03230890


Contacts
Contact: Study Coordinator 336-716-9447 WFHIRREM@wakehealth.edu

Locations
United States, North Carolina
Wake Forest School of Medicine Recruiting
Winston-Salem, North Carolina, United States, 27157
Contact: Study Coordinator    336-716-9447    WFHIRREM@wakehealth.edu   
Sponsors and Collaborators
Wake Forest University Health Sciences
Brain State Technologies, LLC
Investigators
Principal Investigator: Charles H Tegeler, MD Wake Forest University Health Sciences
  Study Documents (Full-Text)

Documents provided by Wake Forest University Health Sciences:
Informed Consent Form  [PDF] January 7, 2015


Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Wake Forest University Health Sciences
ClinicalTrials.gov Identifier: NCT03230890     History of Changes
Other Study ID Numbers: IRB00028990
First Posted: July 27, 2017    Key Record Dates
Last Update Posted: November 7, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: Yes
Pediatric Postmarket Surveillance of a Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Wake Forest University Health Sciences:
PTSD
military
neurotechnology
HIRREM
allostasis
heart rate variability
baroreflex sensitivity
closed loop
acoustic stimulation
neural oscillations
autonomic
hyperarousal

Additional relevant MeSH terms:
Stress Disorders, Post-Traumatic
Stress Disorders, Traumatic
Trauma and Stressor Related Disorders
Mental Disorders