<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04493775</url>
  </required_header>
  <id_info>
    <org_study_id>NHS001675</org_study_id>
    <nct_id>NCT04493775</nct_id>
  </id_info>
  <brief_title>Smartphone-based Brainwave Entrainment (BWE) Technology in Chronic Pain</brief_title>
  <official_title>A Feasibility Study of Smartphone-based Brainwave Entrainment (BWE) Technology as a Novel Treatment for Chronic Pain</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Helen Locke</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Leeds</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Manchester</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Is brainwave entrainment a feasible tool for managing long-term pain in a patient population&#xD;
      in the home-setting? Long-term pain affects 4 in 10 people in the UK and can impact on all&#xD;
      aspects of life. Many people find that their pain is not well controlled on the treatments&#xD;
      that are currently available, or they experience unpleasant side-effects from painkillers.&#xD;
      There is therefore an urgent need for new safe and effective treatments for long-term pain.&#xD;
&#xD;
      One new approach to treatment is to target alpha brainwaves - rhythmic brain activity that is&#xD;
      known to be associated with reduced pain. Alpha brainwaves can be increased by looking at&#xD;
      flashing lights or listening to rhythmic sounds at the same rhythm as the brainwaves. This is&#xD;
      known as &quot;brainwave entrainment&quot; (BWE) and can be delivered through a smartphone application.&#xD;
&#xD;
      The aim of this study is to test the suitability, acceptability and benefits of the brainwave&#xD;
      entrainment smartphone application for people with long-term pain, and to inform the design&#xD;
      of a future larger study.&#xD;
&#xD;
      The investigators aim to recruit 40 participants. Individuals may be eligible if they are&#xD;
      over 18 years old and have suffered persistent pain for longer than 3 months. Participants&#xD;
      will attend a 3-hour session in the laboratory in either Manchester or Leeds. They will&#xD;
      undergo brainwave entrainment for different lengths of time whilst their brain activity and&#xD;
      pain levels are recorded to determine the most effective &quot;dose&quot; of entrainment for that&#xD;
      individual. They will then use the smartphone application at home 3 times a day for 4 weeks,&#xD;
      and will complete pain, sleep, fatigue and quality of life questionnaires. At the end of the&#xD;
      study, the investigators will conduct interviews to gain in-depth feedback. The total&#xD;
      duration for each participant is around 7 weeks. This study is funded by a Leeds Cares&#xD;
      Clinical Research Fellowship.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Primary Question/Objective:&#xD;
&#xD;
      The principal research objectives are two-fold:&#xD;
&#xD;
        -  Firstly, to understand the dose-response of alpha BWE.&#xD;
&#xD;
        -  Secondly, to test the feasibility of using alpha BWE technology for managing chronic&#xD;
           pain in the home environment and to inform the design of a future clinical trial.&#xD;
&#xD;
      Secondary Question/Objective:&#xD;
&#xD;
        -  To identify any issues with recruitment or retention of participants.&#xD;
&#xD;
        -  To test the acceptability and usability of the intervention.&#xD;
&#xD;
        -  To test the acceptability of the outcome measures and methods of data collection.&#xD;
&#xD;
        -  To gain an understanding of the effect size in order to calculate how many participants&#xD;
           will be required for a future clinical trial.&#xD;
&#xD;
      STUDY DESIGN&#xD;
&#xD;
      Participants:&#xD;
&#xD;
      A total of 40 participants will be recruited from musculoskeletal, rheumatology and&#xD;
      rehabilitation clinics in Leeds Teaching Hospitals National Health Service (NHS) Trust and&#xD;
      Salford Royal NHS Foundation Trust.&#xD;
&#xD;
      Study Intervention and Procedures:&#xD;
&#xD;
      This is a two-stage feasibility study incorporating electroencephalography (EEG),&#xD;
      quantitative outcome measures and qualitative interviews.&#xD;
&#xD;
      Project duration:&#xD;
&#xD;
      Each participant's involvement is estimated to last a minimum of 7 weeks (this may be longer&#xD;
      depending on the availability of the participant to attend laboratory sessions).&#xD;
&#xD;
      Number of centres:&#xD;
&#xD;
      This study will be conducted across two sites: University of Manchester and University of&#xD;
      Leeds. Two NHS sites will act as Participant Identification Centres (PICs): Leeds Teaching&#xD;
      Hospitals Trust and Salford Royal NHS Foundation Trust.&#xD;
&#xD;
      Study design and procedures:&#xD;
&#xD;
      The project will be comprised of two studies: 1) a laboratory-based study followed by 2) a&#xD;
      home-based study. All participants will be involved in both studies.&#xD;
&#xD;
      Potential participants may be approached and provided with a flyer and Participant&#xD;
      Information Leaflet from musculoskeletal, rehabilitation and pain clinics at the two PICs, or&#xD;
      may find out about the study from flyers placed in relevant NHS clinics or other relevant&#xD;
      settings such as support groups. The participant will then contact the research team by phone&#xD;
      or email on the contact details provided to discuss the study further, go through the&#xD;
      screening process and arrange a convenient time for them to attend the laboratory if they&#xD;
      wish to proceed.&#xD;
&#xD;
      Study 1:&#xD;
&#xD;
      Participants will attend either the University of Manchester laboratory in Salford Royal&#xD;
      Hospital, or the University of Leeds laboratory in the School of Biological Sciences,&#xD;
      University of Leeds, whichever is more convenient. They will be given opportunity to ask any&#xD;
      questions before signing the consent forms. They will complete the following questionnaires:&#xD;
&#xD;
        -  demographics form (5-10 mins)&#xD;
&#xD;
        -  Pittsburg Sleep Quality Index (PSQI) (5-10 mins)&#xD;
&#xD;
        -  Multidimensional Fatigue Index (MFI) (5-10 mins)&#xD;
&#xD;
        -  EuroQol Five Dimensions (EQ-5D) (5-10 mins) Baseline EEG will be recorded for 7 minutes.&#xD;
           The participant will then undergo 4 blocks of visual or auditory rhythmic stimulation (3&#xD;
           blocks of 10Hz visual stimulation lasting 5, 15 and 30 minutes and 1 block of&#xD;
           non-entraining visual stimulation lasting 10 minutes) with 10-minute breaks in between&#xD;
           as a wash-out period. EEG will continue to be recorded during these breaks. Participants&#xD;
           will complete a Numerical Rating Scale (NRS) for pain intensity and unpleasantness&#xD;
           before and after each block (&lt;1 min). EEG will be recorded throughout stimulation.&#xD;
&#xD;
      Participants will then be introduced to the smartphone app, shown how to use it and given the&#xD;
      opportunity to practice (30 mins). Participants will be provided with a smartphone with the&#xD;
      BWE app pre-downloaded, a Virtual Reality (VR) headset and set of earphones to use for the&#xD;
      duration of the study.&#xD;
&#xD;
      The estimated total laboratory time is 3 hours.&#xD;
&#xD;
      Study 2:&#xD;
&#xD;
      Participants will be asked to record NRS 3x a day and Brief Pain Index (BPI) short form (5-10&#xD;
      mins) 1x a day for 1 week at home to get baseline pain levels. After this period, they will&#xD;
      be contacted by phone or email by a researcher to remind them to begin using the stimulation.&#xD;
      They will then use the stimulation 3x a day for the specific duration that was identified as&#xD;
      the optimum for them during the laboratory-based study (i.e. 5, 15 or 30 minutes, based on&#xD;
      clinical pain ratings) for 4 weeks. They will record NRS for pain intensity and&#xD;
      unpleasantness before and after each stimulation and BPI at the end of each day. This will be&#xD;
      followed by a further week of baseline pain ratings with NRS 3x a day and BPI once a day.&#xD;
&#xD;
      Following this, the participant will attend the laboratory at a pre-arranged time to complete&#xD;
      the following questionnaires:&#xD;
&#xD;
        -  PSQI&#xD;
&#xD;
        -  MFI&#xD;
&#xD;
        -  EQ-5D (see study 1 for timings).&#xD;
&#xD;
      They will also participate in a semi-structured interview (&lt;45 minutes) with a researcher.&#xD;
      The interview will be based around a topic guide, however the semi-structured approach will&#xD;
      allow for trajectories in the conversation according to any significant or relevant topics&#xD;
      that may arise. The topic guide will be designed to:&#xD;
&#xD;
        1. Elicit participants' experiences of interacting with the app including factors affecting&#xD;
           usability, adherence, the extent to which there has been any change in symptoms, any&#xD;
           side effects and overall perceived usefulness and acceptability.&#xD;
&#xD;
        2. Explore any feasibility and process issues including factors affecting completion of&#xD;
           outcome measures.&#xD;
&#xD;
      The interview will be audio-recorded and then transcribed verbatim with any identifiable data&#xD;
      removed from the transcripts.&#xD;
&#xD;
      Recruitment:&#xD;
&#xD;
      Flyers advertising the study will be placed in relevant rheumatology, musculoskeletal and&#xD;
      rehabilitation NHS clinics in Leeds and Manchester and in non-clinical settings (including&#xD;
      support groups). Potential participants may be approached by clinicians in NHS clinics in the&#xD;
      PICS, or they may contact the study team by telephone or email on the contact information&#xD;
      provided on leaflets. Their eligibility for the study will be assessed by telephone.&#xD;
      Participants will be provided with a verbal explanation and a Participant Information Leaflet&#xD;
      (PIL) explaining the study, either in person or by email/post. They will have a minimum of 24&#xD;
      hours to decide whether to participate, at which point an initial meeting will be scheduled&#xD;
      at a convenient date and time for the participant.&#xD;
&#xD;
      Written informed consent will be obtained from participants when they attend the laboratory&#xD;
      for the initial meeting. Participants will have the opportunity to ask any further questions&#xD;
      prior to consenting. A copy of the signed consent form will be given to the participant for&#xD;
      their records and the original copy will be securely filed.&#xD;
&#xD;
      Randomisation:&#xD;
&#xD;
      All participants will receive the same intervention, however for study 1, the order in which&#xD;
      the four sessions of stimulation (5, 15, 30 mins of alpha frequency and 10 mins of&#xD;
      non-entraining stimulation) are delivered will be randomised using computer generated random&#xD;
      numbers. A single research assistant who is not involved in delivery of the intervention will&#xD;
      be responsible for the randomisation process. Neither the researcher delivering the&#xD;
      intervention nor the participant will know the selected sequence at the start, however, it&#xD;
      will not be possible for either the researcher or the participant to be completely blinded,&#xD;
      given that the differences in duration of stimulation are likely to be quite apparent.&#xD;
&#xD;
      Statistical Analysis EEG data will be analysed using BrainVision Analyzer 2.0. Source&#xD;
      localisation will be estimated using low resolution electromagnetic tomography (LORETA) using&#xD;
      LORETA-KEY software. Appropriate statistical analysis will be carried out using SPSS&#xD;
      software.&#xD;
&#xD;
      Interview findings will be explored with thematic content analysis using a Template Analysis&#xD;
      approach. This involves the definition of a priori themes relevant to the research question.&#xD;
      Two researchers will separately review and code an initial five transcripts based on the a&#xD;
      priori themes, before coming together to organise the emerging themes into meaningful&#xD;
      clusters and create an initial coding template by which to analyse the rest of the&#xD;
      transcripts (modifying and revising the template as further themes emerge).&#xD;
&#xD;
      Sample Size:&#xD;
&#xD;
      The investigators aim to recruit a total of 40 participants who will take part in both work&#xD;
      package 1 and 2. As a feasibility study, one of the key aims is to gain data on effect size&#xD;
      in order to calculate sample size for a future clinical trial. Therefore, the sample size is&#xD;
      based on previous studies as well as considering pragmatics such as funding, equipment and&#xD;
      time available.&#xD;
&#xD;
      DATA MONITORING AND QUALITY ASSURANCE The study will be subject to the audit and monitoring&#xD;
      regime of the Universities of Manchester and Leeds.&#xD;
&#xD;
      SAFETY CONSIDERATIONS AND ADVERSE EVENTS This study uses alpha frequency brainwave&#xD;
      entrainment, which has no known significant side effects or risks. Therefore, the anticipated&#xD;
      risk to participants is considered to be very low.&#xD;
&#xD;
      There are no anticipated risks to the researchers. There will be two-weekly debriefs with the&#xD;
      whole research team to address any potential issues. There will be no lone-working for any&#xD;
      team member.&#xD;
&#xD;
      ETHICAL and REGULATORY CONSIDERATIONS&#xD;
&#xD;
      Approvals:&#xD;
&#xD;
      The study will be conducted in full conformance with all relevant legal requirements and the&#xD;
      principles of the Declaration of Helsinki, Good Clinical Practice (GCP) and the UK Policy&#xD;
      Framework for Health and Social Care Research 2017. The study will be approved by NHS&#xD;
      Research Ethics Committee and Health Research Authority prior to commencement.&#xD;
&#xD;
      Potential risks and burden to participants:&#xD;
&#xD;
      Due to the rhythmic flashing lights of the visual stimulation, individuals with a history of&#xD;
      epilepsy or seizures will be excluded from the study, to mitigate the risk of triggering&#xD;
      seizures. Those with sensitivity to flashing lights or a history of migraines or recurrent&#xD;
      headaches will also be excluded. The brightness of the visual stimulation and the volume of&#xD;
      auditory stimulation will be adjustable, to ensure it is comfortable. There are no known side&#xD;
      effects from using this technology, however participants will be instructed to stop using it&#xD;
      if they were to experience any adverse symptoms and to inform the research team.&#xD;
&#xD;
      Potential burden may arise from the inconvenience of attending the laboratory for&#xD;
      face-to-face meetings. These have purposefully been kept to only 2 meetings to reduce this&#xD;
      burden as much as possible. Data collection may be considered burdensome. Questionnaires at&#xD;
      the beginning and end of the study will be completed with a researcher on hand to provide&#xD;
      support. Although the NRS for pain takes seconds to complete, this will require participants&#xD;
      to remember to record their pain scores three times a day. Participants will be provided with&#xD;
      a clearly laid out booklet to assist them. Part of the feasibility aspect of this study is to&#xD;
      assess how easy and acceptable the data collection measures are, so participants' feedback on&#xD;
      the level of burden will be ascertained in the final interview and will guide future study&#xD;
      design. Participants may perceive some burden from the final interview. It is not anticipated&#xD;
      that the content will be upsetting for participants, however it is recognised that&#xD;
      potentially sensitive topics may arise, including discussion of chronic pain and other&#xD;
      symptoms. Participants will be informed that they do not have to answer any questions that&#xD;
      they are uncomfortable with and they may leave the interview at any time without needing to&#xD;
      give a reason.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Not yet recruiting</overall_status>
  <start_date type="Anticipated">October 1, 2021</start_date>
  <completion_date type="Anticipated">October 1, 2024</completion_date>
  <primary_completion_date type="Anticipated">October 1, 2023</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
    <masking_description>Neither the researcher delivering the intervention nor the participant will know the selected sequence at the start, however, it will not be possible for either the researcher or the participant to be completely blinded to the sequence once it is underway, given that the differences in duration of stimulation are likely to be quite apparent.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Numerical pain ratings (NRS)</measure>
    <time_frame>2 years</time_frame>
    <description>0-10 where 0 = no pain and 10 = worst pain. To indicate whether there is a dose-related change in efficacy of BWE.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Qualitative data from semi-structured interviews</measure>
    <time_frame>2 years</time_frame>
    <description>This will answer key feasibility questions to enable planning of a future clinical trial. This will include information on acceptability and usability of the intervention, feedback on the outcome measures used, engagement with the research, process issues including recruitment, and the extent to which they felt the intervention improved their pain.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Electroencephalography data</measure>
    <time_frame>1 year</time_frame>
    <description>Alpha frequency across all scalp electrodes (64 channel) recorded during rest and during alpha brainwave entrainment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pittsburgh sleep quality index (PSQI)</measure>
    <time_frame>2 years</time_frame>
    <description>9 item questionnaire. The component scores are summed to produce a global score (range 0 to 21). Higher scores indicate worse sleep quality.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Multidimensional Fatigue Inventory (MFI)</measure>
    <time_frame>2 years</time_frame>
    <description>20 item questionnaire with each item scored from 1-5. Higher scores indicate a higher fatigue level.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>EuroQol - 5 dimensions (EQ-5D)</measure>
    <time_frame>2 years</time_frame>
    <description>Two components. 1. Health state description, five indicators whereby higher scores indicate better health in the last 24 hours. 2. Visual analogue scale 0-100 whereby 100 = best health imaginable and 0 = worst health imaginable.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Brief Pain Inventory (BPI)</measure>
    <time_frame>2 years</time_frame>
    <description>Questionnaire with two categories: Pain Intensity (worst, least, on average, and currently) and Pain Interference (mood, work, general activity, walking, relationships, enjoyment of life, and sleep). Each category is rated 0-10. 10 = excruciating pain intensity and a complete interference in their life.</description>
  </secondary_outcome>
  <enrollment type="Anticipated">40</enrollment>
  <condition>Chronic Pain</condition>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Brainwave Entrainment</intervention_name>
    <description>Alpha frequency visual and auditory stimulation delivered through a smartphone application, with the use of a virtual reality headset and earphones respectively.</description>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  adults over the age of 18 years (there is no upper age limit as we would want the&#xD;
             intervention to be as inclusive as possible)&#xD;
&#xD;
          -  clinically significant non-cancer-related chronic pain (for which they have sought&#xD;
             medical input) for more than three months' duration&#xD;
&#xD;
          -  willing and able to consent to taking part.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  any history or first-degree relative history of epilepsy or convulsions/seizures&#xD;
&#xD;
          -  discomfort with flashing lights&#xD;
&#xD;
          -  history of recurrent headaches or migraines&#xD;
&#xD;
          -  participants who have difficulty understanding verbal or written English, or who have&#xD;
             cognitive or mental health problems that would prevent them being able to provide&#xD;
             written informed consent&#xD;
&#xD;
          -  planned intervention (surgery, new medications or treatments) during the study period.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jones</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Manchester</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Locke</last_name>
    <phone>01612064266</phone>
    <email>Helen.locke@manchester.ac.uk</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Sivan</last_name>
    <phone>01612064266</phone>
    <email>Manoj.sivan@manchester.ac.uk</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>University of Manchester</name>
      <address>
        <city>Manchester</city>
        <state>Lancashire</state>
        <zip>M13 9PL</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <contact>
      <last_name>Locke</last_name>
      <phone>01612064266</phone>
      <email>Helen.locke@manchester.ac.uk</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>University of Leeds</name>
      <address>
        <city>Leeds</city>
        <state>West Yorkshire</state>
        <zip>LS1 3EX</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <contact>
      <last_name>Sivan</last_name>
      <phone>01612064266</phone>
      <email>Manoj.sivan@manchester.ac.uk</email>
    </contact>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>July 2021</verification_date>
  <study_first_submitted>July 21, 2020</study_first_submitted>
  <study_first_submitted_qc>July 27, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 30, 2020</study_first_posted>
  <last_update_submitted>July 2, 2021</last_update_submitted>
  <last_update_submitted_qc>July 2, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">July 6, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Manchester</investigator_affiliation>
    <investigator_full_name>Helen Locke</investigator_full_name>
    <investigator_title>Clinical Research Fellow</investigator_title>
  </responsible_party>
  <keyword>Alpha rhythm</keyword>
  <keyword>EEG phase synchronisation</keyword>
  <keyword>Mobile applications</keyword>
  <keyword>Pain perception</keyword>
  <keyword>Pain management</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Chronic Pain</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04493775
org study id: NHS001675
nct id: NCT04493775
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Is brainwave entrainment a feasible tool for managing long-term pain in a patient population
      in the home-setting? Long-term pain affects 4 in 10 people in the UK and can impact on all
      aspects of life. Many people find that their pain is not well controlled on the treatments
      that are currently available, or they experience unpleasant side-effects from painkillers.
      There is therefore an urgent need for new safe and effective treatments for long-term pain.

      One new approach to treatment is to target alpha brainwaves - rhythmic brain activity that is
      known to be associated with reduced pain. Alpha brainwaves can be increased by looking at
      flashing lights or listening to rhythmic sounds at the same rhythm as the brainwaves. This is
      known as "brainwave entrainment" (BWE) and can be delivered through a smartphone application.

      The aim of this study is to test the suitability, acceptability and benefits of the brainwave
      entrainment smartphone application for people with long-term pain, and to inform the design
      of a future larger study.

      The investigators aim to recruit 40 participants. Individuals may be eligible if they are
      over 18 years old and have suffered persistent pain for longer than 3 months. Participants
      will attend a 3-hour session in the laboratory in either Manchester or Leeds. They will
      undergo brainwave entrainment for different lengths of time whilst their brain activity and
      pain levels are recorded to determine the most effective "dose" of entrainment for that
      individual. They will then use the smartphone application at home 3 times a day for 4 weeks,
      and will complete pain, sleep, fatigue and quality of life questionnaires. At the end of the
      study, the investigators will conduct interviews to gain in-depth feedback. The total
      duration for each participant is around 7 weeks. This study is funded by a Leeds Cares
      Clinical Research Fellowship.
Primary Question/Objective:

      The principal research objectives are two-fold:

        -  Firstly, to understand the dose-response of alpha BWE.

        -  Secondly, to test the feasibility of using alpha BWE technology for managing chronic
           pain in the home environment and to inform the design of a future clinical trial.

      Secondary Question/Objective:

        -  To identify any issues with recruitment or retention of participants.

        -  To test the acceptability and usability of the intervention.

        -  To test the acceptability of the outcome measures and methods of data collection.

        -  To gain an understanding of the effect size in order to calculate how many participants
           will be required for a future clinical trial.

      STUDY DESIGN

      Participants:

      A total of 40 participants will be recruited from musculoskeletal, rheumatology and
      rehabilitation clinics in Leeds Teaching Hospitals National Health Service (NHS) Trust and
      Salford Royal NHS Foundation Trust.

      Study Intervention and Procedures:

      This is a two-stage feasibility study incorporating electroencephalography (EEG),
      quantitative outcome measures and qualitative interviews.

      Project duration:

      Each participant's involvement is estimated to last a minimum of 7 weeks (this may be longer
      depending on the availability of the participant to attend laboratory sessions).

      Number of centres:

      This study will be conducted across two sites: University of Manchester and University of
      Leeds. Two NHS sites will act as Participant Identification Centres (PICs): Leeds Teaching
      Hospitals Trust and Salford Royal NHS Foundation Trust.

      Study design and procedures:

      The project will be comprised of two studies: 1) a laboratory-based study followed by 2) a
      home-based study. All participants will be involved in both studies.

      Potential participants may be approached and provided with a flyer and Participant
      Information Leaflet from musculoskeletal, rehabilitation and pain clinics at the two PICs, or
      may find out about the study from flyers placed in relevant NHS clinics or other relevant
      settings such as support groups. The participant will then contact the research team by phone
      or email on the contact details provided to discuss the study further, go through the
      screening process and arrange a convenient time for them to attend the laboratory if they
      wish to proceed.

      Study 1:

      Participants will attend either the University of Manchester laboratory in Salford Royal
      Hospital, or the University of Leeds laboratory in the School of Biological Sciences,
      University of Leeds, whichever is more convenient. They will be given opportunity to ask any
      questions before signing the consent forms. They will complete the following questionnaires:

        -  demographics form (5-10 mins)

        -  Pittsburg Sleep Quality Index (PSQI) (5-10 mins)

        -  Multidimensional Fatigue Index (MFI) (5-10 mins)

        -  EuroQol Five Dimensions (EQ-5D) (5-10 mins) Baseline EEG will be recorded for 7 minutes.
           The participant will then undergo 4 blocks of visual or auditory rhythmic stimulation (3
           blocks of 10Hz visual stimulation lasting 5, 15 and 30 minutes and 1 block of
           non-entraining visual stimulation lasting 10 minutes) with 10-minute breaks in between
           as a wash-out period. EEG will continue to be recorded during these breaks. Participants
           will complete a Numerical Rating Scale (NRS) for pain intensity and unpleasantness
           before and after each block (<1 min). EEG will be recorded throughout stimulation.

      Participants will then be introduced to the smartphone app, shown how to use it and given the
      opportunity to practice (30 mins). Participants will be provided with a smartphone with the
      BWE app pre-downloaded, a Virtual Reality (VR) headset and set of earphones to use for the
      duration of the study.

      The estimated total laboratory time is 3 hours.

      Study 2:

      Participants will be asked to record NRS 3x a day and Brief Pain Index (BPI) short form (5-10
      mins) 1x a day for 1 week at home to get baseline pain levels. After this period, they will
      be contacted by phone or email by a researcher to remind them to begin using the stimulation.
      They will then use the stimulation 3x a day for the specific duration that was identified as
      the optimum for them during the laboratory-based study (i.e. 5, 15 or 30 minutes, based on
      clinical pain ratings) for 4 weeks. They will record NRS for pain intensity and
      unpleasantness before and after each stimulation and BPI at the end of each day. This will be
      followed by a further week of baseline pain ratings with NRS 3x a day and BPI once a day.

      Following this, the participant will attend the laboratory at a pre-arranged time to complete
      the following questionnaires:

        -  PSQI

        -  MFI

        -  EQ-5D (see study 1 for timings).

      They will also participate in a semi-structured interview (<45 minutes) with a researcher.
      The interview will be based around a topic guide, however the semi-structured approach will
      allow for trajectories in the conversation according to any significant or relevant topics
      that may arise. The topic guide will be designed to:

        1. Elicit participants' experiences of interacting with the app including factors affecting
           usability, adherence, the extent to which there has been any change in symptoms, any
           side effects and overall perceived usefulness and acceptability.

        2. Explore any feasibility and process issues including factors affecting completion of
           outcome measures.

      The interview will be audio-recorded and then transcribed verbatim with any identifiable data
      removed from the transcripts.

      Recruitment:

      Flyers advertising the study will be placed in relevant rheumatology, musculoskeletal and
      rehabilitation NHS clinics in Leeds and Manchester and in non-clinical settings (including
      support groups). Potential participants may be approached by clinicians in NHS clinics in the
      PICS, or they may contact the study team by telephone or email on the contact information
      provided on leaflets. Their eligibility for the study will be assessed by telephone.
      Participants will be provided with a verbal explanation and a Participant Information Leaflet
      (PIL) explaining the study, either in person or by email/post. They will have a minimum of 24
      hours to decide whether to participate, at which point an initial meeting will be scheduled
      at a convenient date and time for the participant.

      Written informed consent will be obtained from participants when they attend the laboratory
      for the initial meeting. Participants will have the opportunity to ask any further questions
      prior to consenting. A copy of the signed consent form will be given to the participant for
      their records and the original copy will be securely filed.

      Randomisation:

      All participants will receive the same intervention, however for study 1, the order in which
      the four sessions of stimulation (5, 15, 30 mins of alpha frequency and 10 mins of
      non-entraining stimulation) are delivered will be randomised using computer generated random
      numbers. A single research assistant who is not involved in delivery of the intervention will
      be responsible for the randomisation process. Neither the researcher delivering the
      intervention nor the participant will know the selected sequence at the start, however, it
      will not be possible for either the researcher or the participant to be completely blinded,
      given that the differences in duration of stimulation are likely to be quite apparent.

      Statistical Analysis EEG data will be analysed using BrainVision Analyzer 2.0. Source
      localisation will be estimated using low resolution electromagnetic tomography (LORETA) using
      LORETA-KEY software. Appropriate statistical analysis will be carried out using SPSS
      software.

      Interview findings will be explored with thematic content analysis using a Template Analysis
      approach. This involves the definition of a priori themes relevant to the research question.
      Two researchers will separately review and code an initial five transcripts based on the a
      priori themes, before coming together to organise the emerging themes into meaningful
      clusters and create an initial coding template by which to analyse the rest of the
      transcripts (modifying and revising the template as further themes emerge).

      Sample Size:

      The investigators aim to recruit a total of 40 participants who will take part in both work
      package 1 and 2. As a feasibility study, one of the key aims is to gain data on effect size
      in order to calculate sample size for a future clinical trial. Therefore, the sample size is
      based on previous studies as well as considering pragmatics such as funding, equipment and
      time available.

      DATA MONITORING AND QUALITY ASSURANCE The study will be subject to the audit and monitoring
      regime of the Universities of Manchester and Leeds.

      SAFETY CONSIDERATIONS AND ADVERSE EVENTS This study uses alpha frequency brainwave
      entrainment, which has no known significant side effects or risks. Therefore, the anticipated
      risk to participants is considered to be very low.

      There are no anticipated risks to the researchers. There will be two-weekly debriefs with the
      whole research team to address any potential issues. There will be no lone-working for any
      team member.

      ETHICAL and REGULATORY CONSIDERATIONS

      Approvals:

      The study will be conducted in full conformance with all relevant legal requirements and the
      principles of the Declaration of Helsinki, Good Clinical Practice (GCP) and the UK Policy
      Framework for Health and Social Care Research 2017. The study will be approved by NHS
      Research Ethics Committee and Health Research Authority prior to commencement.

      Potential risks and burden to participants:

      Due to the rhythmic flashing lights of the visual stimulation, individuals with a history of
      epilepsy or seizures will be excluded from the study, to mitigate the risk of triggering
      seizures. Those with sensitivity to flashing lights or a history of migraines or recurrent
      headaches will also be excluded. The brightness of the visual stimulation and the volume of
      auditory stimulation will be adjustable, to ensure it is comfortable. There are no known side
      effects from using this technology, however participants will be instructed to stop using it
      if they were to experience any adverse symptoms and to inform the research team.

      Potential burden may arise from the inconvenience of attending the laboratory for
      face-to-face meetings. These have purposefully been kept to only 2 meetings to reduce this
      burden as much as possible. Data collection may be considered burdensome. Questionnaires at
      the beginning and end of the study will be completed with a researcher on hand to provide
      support. Although the NRS for pain takes seconds to complete, this will require participants
      to remember to record their pain scores three times a day. Participants will be provided with
      a clearly laid out booklet to assist them. Part of the feasibility aspect of this study is to
      assess how easy and acceptable the data collection measures are, so participants' feedback on
      the level of burden will be ascertained in the final interview and will guide future study
      design. Participants may perceive some burden from the final interview. It is not anticipated
      that the content will be upsetting for participants, however it is recognised that
      potentially sensitive topics may arise, including discussion of chronic pain and other
      symptoms. Participants will be informed that they do not have to answer any questions that
      they are uncomfortable with and they may leave the interview at any time without needing to
      give a reason.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
masking description: Neither the researcher delivering the intervention nor the participant will know the selected sequence at the start, however, it will not be possible for either the researcher or the participant to be completely blinded to the sequence once it is underway, given that the differences in duration of stimulation are likely to be quite apparent.
measure: Numerical pain ratings (NRS)
time frame: 2 years
description: 0-10 where 0 = no pain and 10 = worst pain. To indicate whether there is a dose-related change in efficacy of BWE.
measure: Qualitative data from semi-structured interviews
time frame: 2 years
description: This will answer key feasibility questions to enable planning of a future clinical trial. This will include information on acceptability and usability of the intervention, feedback on the outcome measures used, engagement with the research, process issues including recruitment, and the extent to which they felt the intervention improved their pain.
measure: Electroencephalography data
time frame: 1 year
description: Alpha frequency across all scalp electrodes (64 channel) recorded during rest and during alpha brainwave entrainment.
measure: Pittsburgh sleep quality index (PSQI)
time frame: 2 years
description: 9 item questionnaire. The component scores are summed to produce a global score (range 0 to 21). Higher scores indicate worse sleep quality.
measure: Multidimensional Fatigue Inventory (MFI)
time frame: 2 years
description: 20 item questionnaire with each item scored from 1-5. Higher scores indicate a higher fatigue level.
measure: EuroQol - 5 dimensions (EQ-5D)
time frame: 2 years
description: Two components. 1. Health state description, five indicators whereby higher scores indicate better health in the last 24 hours. 2. Visual analogue scale 0-100 whereby 100 = best health imaginable and 0 = worst health imaginable.
measure: Brief Pain Inventory (BPI)
time frame: 2 years
description: Questionnaire with two categories: Pain Intensity (worst, least, on average, and currently) and Pain Interference (mood, work, general activity, walking, relationships, enjoyment of life, and sleep). Each category is rated 0-10. 10 = excruciating pain intensity and a complete interference in their life.
intervention type: Device
intervention name: Brainwave Entrainment
description: Alpha frequency visual and auditory stimulation delivered through a smartphone application, with the use of a virtual reality headset and earphones respectively.
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Jones
role: Principal Investigator
affiliation: University of Manchester
last name: Locke
phone: 01612064266
email: Helen.locke@manchester.ac.uk
last name: Sivan
phone: 01612064266
email: Manoj.sivan@manchester.ac.uk
facility: 
contact: 
facility: 
contact: 
country: United Kingdom
responsible party type: Sponsor-Investigator
investigator affiliation: University of Manchester
investigator full name: Helen Locke
investigator title: Clinical Research Fellow
mesh term: Chronic Pain
sharing ipd: No