The objective of this study is to investigate the efficacy and safety of a 12-week daily use of the Cerebri biofeedback device as compared to a waitlist control in adults with episodic migraine.

Primary efficacy endpoint

The primary endpoint is the change in the mean number of migraine days from baseline to the last 28-day period (week 9–12) during the treatment phase in the treatment group compared to the wait-list control group.

Secondary efficacy endpoints

The key secondary endpoint analyses are changes in mean number of migraine days in week 1–4 and week 5–8, change in mean migraine intensity, proportion of 30% responders, change in acute migraine drug treatment use, and change in subject-reported headache-related disability. Exploratory and descriptive endpoints include changes in weekly migraine days, mean headache days per 28-day period, eDiary and biofeedback session adherence, and mean Patient Global Impression of Change (PGI-C) scores. Additionally, changes in the mean number of migraine days during the extended biofeedback period will be assessed.

Safety endpoints

Description of the frequency and severity of treatment-emergent adverse events (AEs), adverse device effects (ADEs), serious adverse device effects (SADEs), and unexpected serious adverse side effects (USADEs) is included. In the case of pregnant participants, at inclusion or acknowledged during participation, no additional monitoring of maternal or fetal health is instituted. In such cases, participants are asked if they agree to be followed up until the end of pregnancy to collect data on any pregnancy complications and fetal outcome data.

This is an open-label, randomized, waitlist-controlled, multicenter trial. The study design follows the standard for clinical investigation of medical devices for human subjects – good clinical practice (ISO 14155:2020) – and the relevant trial guidelines of the International Headache Society. ¹² Reporting follows the CONSORT guidelines.

The total duration of study participation is 16 weeks, with the possibility of a 12-week extension period ( Figure 1). After the screening visit, if eligible, the participants are assigned to a baseline period of a minimum of four weeks in accordance with the guidelines. ¹² During the baseline period, participants maintain a daily headache diary in the Cerebri smartphone app. Upon completion of the baseline period, the participants were rescreened for eligibility prior to randomization. This design, where the baseline period also serves as a screening period, enables rescreening based on eDiary entries. This is the recommended approach for enrolling RCTs on episodic migraine. ¹² Participants deemed ineligible at the point of rescreening, or who withdraw from or are lost to follow-up during the baseline period, are categorized as screening failures and are excluded from further participation.

Eligible participants are randomly allocated to the treatment or waitlist groups. The treatment group receives the medical device by postal service, and a treatment period of 12 weeks is initiated on the first day of completing a biofeedback session. Participants in the waitlist group complete daily eDiary entries for 12 weeks from the day of randomization.

Both arms are invited to participate for a 12-week extension period. Participants randomly allocated to the waiting list are offered the possibility of entering a 12-week extension phase with biofeedback treatment. The 12-week extension period is initiated on the first day of the biofeedback training. The participants randomized to the intervention group are invited to a 12-week extension period after completing their 12-week biofeedback treatment, in which they continue with daily eDairy only.

Participants will not have access to the intervention at the end of the study. Beyond the voluntary 12-week extension period, there will be no long-term follow-up on safety and survival status, except in cases of pregnancy.

Random group allocation occurs a minimum of four weeks after inclusion and after rescreening. If eligible, permuted block randomization is performed. Randomization is stratified on the adjunct use of preventive medication.

Blinding/masking is not possible owing to the nature of the intervention in question and is thus not performed.

This trial recruits participants from all over Norway, with inclusion sites covering all health regions. The investigational sites are the neurological departments at St. Olavs Hospital, Trondheim University Hospital, Akershus University Hospital, Haukeland University Hospital, and University Hospital of North Norway. Visits 1 (baseline inclusion) and 2 (rescreening and randomization) are performed by medical doctors with headache expertise. All visits are conducted remotely via video or telephone. Information about the trial and contact information to indicate interest in participation is disseminated through relevant institution webpages and social media platforms. Interested parties may contact the study site directly via email or may be referred. Study personnel are prohibited from enrolling patients for whom they were primarily responsible for treatment and/or follow-up.

A full list of the inclusion and exclusion criteria is listed in Table 1. Eligibility is assessed at visits 1 and 2 ( Figure 1), and participants must comply with all inclusion criteria and none of the exclusion criteria to proceed to randomization. Participants are allowed to use one preventive migraine medication if they are stable upon study entry and remain unaltered during study participation. In the case of onabotulinum toxin A injections following the PREEMT injection paradigm, a stable treatment regimen is operationalised as at least three consecutive treatments prior to inclusion. All preventive treatments in use was initiated as part of previous management prior to study entry, and this clinical follow up was continued during trial participation. For other prophylactic treatments, a duration of three months or five half-lives, whichever is longer, of unaltered use is considered stable.

This study is conducted in accordance with the principles of ISO 14155:2020 (Clinical Investigation of Medical Devices in Human Subjects), Good Clinical practice, and the Guidelines of the International Headache Society. The study is approved by the Regional Committees for Medical Research Ethics (REK, approval number 502734. Date of approval 2022-10-14) and the Norwegian Medical Product Agency (NOMA) (reference number 22/17254-5. Date of approval 2022-09-01) prior to initiation. Substantial protocol amendments will be reviewed by competent authorities before implementation. Data protection follows the GDPR. We adhere to the Declaration of Helsinki.

To ensure that all subjects have similar opportunities to benefit from enrolment, participants randomized to the waitlist group are offered treatment following the conclusion of the waitlist period. Consent is collected by the investigator conducting the screening visit. Study information is sent in advance of visit 1 by email, scripted study information is provided orally, and any questions are addressed during visit 1 prior to signing to ensure that consent is obtained in all cases. Consent is collected by a digital signature via a national electronic data entry application («Helsenorge»). Study personnel are prohibited from recruiting patients for whom they are directly responsible for treatment.

Investigational medical device

The medical device Cerebri consists of a smartphone app and a set of two wireless non-invasive sensors. Both sensors are skin-contact-dependent. One sensor is attached to the index finger and measures HRV and peripheral skin temperature. The second sensor is attached to the skin over the upper trapezius muscle fibers using adhesive electrodes and measures muscle tension as surface electromyographic voltage ( Figure 2A and 2B). The sensors transmit the measurements to the user’s smartphone by Bluetooth technology and display them in real time to the user. Participants receive the sensors by mail together with a brief written onboarding guide. All training is delivered in a standardised, app-based format without individualised or therapist-led instruction. The app guides users through the first three biofeedback sessions, and provides a library with textual instructions on exercises that the user can choose to use in their biofeedback training. By following instructions for suggested exercises displayed in the Cerebri smartphone app, the subject trains on influencing the measured parameters in the desired direction during each biofeedback session. Figure 3A-C illustrate how visualization of the physiological measures is displayed on their smartphone. Exercises to facilitate successful manipulation of the physiological parameters include breathing techniques, progressive muscle relaxation, and awareness training. A visual breathing pacer to support paced breathing is available in the mobile app to the user during the entire treatment session. It is desirable to increase HRV and peripheral skin temperature and lower neck muscle tension. Participants are instructed to sit comfortably in a quiet room during treatment. Throughout the intervention period, participants are required to complete a 10-minute biofeedback session at least once daily at a time of their choosing. They have the option to perform as many as six sessions each day.

eDiary and biofeedback

Data on headache is collected prospectively as a patient-reported outcome measure in an eDiary integrated into the Cerebri smartphone app. Daily entries are encouraged, but the app allows the entry of registrations from the two previous calendar days. The app includes daily reminders to promote adherence. The tool is designed such that when participants report headaches, they are prompted to answer additional questions. Data collected in the diary include the estimated duration of headache, intensity of headache using an 11-point scale (0-10), and the use (type, dose, and number of administrations) of acute medications (triptan, paracetamol, NSAIDs, opioids, other), and information on whether acute medications relieved headache ( Table 2 and Figure 4A and 4B). Participants are followed up with telephone calls at week 2, week 4 and week 8 to promote adherence ( Figure 1).

A web-based dashboard solution enables study personnel to access a real-time overview of adherence to eDiary and biofeedback treatment. Thus, study personnel can identify and reach out to participants with low adherence. In the case of technical issues, a support service provided by the sponsor is available. The dashboard also includes information regarding the migraine/headache status on a given day and acute medication use. This information will be accessible to study personnel in the baseline period for rescreening purposes. Post randomization, only the adherence data is available.

Questionnaires

Subjects are asked to complete validated questionnaires at the end of each 28-day period to measure the headache-related impact on the quality of life and their impression of treatment efficacy. The questionnaires used in this trial are the Migraine-Specific Quality-of-Life Questionnaire (MSQ) v2.1 ¹³ and the Patient Global Impression of Change (PGI-C). ¹⁴ The MSQ is copyrighted and registered with the United States Library of Congress by Glaxo Wellcome, Inc. A written permission for use is obtained prior to use.

Electronic patient record

Patient records are the source of information regarding medical history, current medications in use, and previous trials of prophylactic migraine treatment acquired during visit 1. Alterations in health status, including treatment-emergent adverse events during trial participation are registered in the medical records.

Study-specific electronic case report form (eCRF)

An eCRF applying the WebCRF3 software (version 3) ( https://webcrf3.medisin.ntnu.no) was developed for this study. The webCRF software is provided and maintained by the Unit for Applied Clinical Research (AKF) at the Faculty of Medicine and Health Sciences, NTNU. Data collected during study visits, telephone consultations, and safety information are entered. Data are stored in a pseudo-anonymous manner, and each study participant is identified using a unique study identification (ID) number. An open-source alternative OpenClinica ( https://www.openclinica.com/get-free-community-edition-software) is able to perform an equivalent function as WebCRF3.

Study monitoring

No data-monitoring committee is appointed for this study. An independent Data Monitor will be used for review of the study in accordance with a Monitoring Plan.

Data management

Data management is guided by the data management plan. Data validation and verification of a minimum of 10% of participants will be conducted before data lock. Data lock can be performed when the last participant ends its 12 week post-randomization period, that is, while the participants are still in an extension period.

Research hypothesis

The primary endpoint is to investigate the change in the mean number of migraine days from baseline to the last 28-day period in the treatment group compared with the wait-list control group. Thus, the null hypothesis (H0) and alternative hypothesis (H1) to be tested in relation to the primary objective are as follows. •

H0: The change in the mean number of migraine days from the 28-day baseline to the last 28-day period in the treatment group is equal to the change in the mean number of migraine days from baseline to the last 28-day period in the wait-list control group.

vs. •

H1: The change in the mean number of migraine days from the 28-day baseline to the last 28-day period in the treatment group is not equal to the change in the mean number of migraine days from baseline to the last 28-day period in the wait-list control group.

Sample size

The sample size calculation is based on an assumption of the effect size derived from a relevant meta-analysis of the efficacy of biofeedback in treating migraine ¹⁵ and a randomized pilot study. ⁹ Provided an effect size of d = 0.4, a significance level alpha of 0.05 (two-sided), power 0.8, and a dropout rate of 30% in the post-randomization period, the required sample size of this study was estimated to 286 participants. The anticipation of high dropout rates in this study is justified in the significant challenge of maintaining participant adherence observed in home-based mHealth studies. ^{9 , 16}

Protocol deviations

Participants with incomplete or missing headache diary entries in more than 30% of days in the post-randomization period, participants with more than 30% missing or incomplete biofeedback sessions in the treatment arm, and participants initiating new or altering the use of their established preventive headache medications during the trial, are considered protocol deviators.

Statistical analysis plan

The statistical analysis plan (SAP) will include a technical and detailed description of statistical analysis. Statistical analyses will be conducted by an independent statistician. The analysis will follow a predefined order, where the primary efficacy endpoint is analyzed first. The trial statistician will analyze the efficacy outcomes without knowledge of treatment allocation by using a dataset with study arm allocation coded as groups A and B.

Data analysis set

For the efficacy analysis, the full analysis set includes all randomized participants and constitutes the intention-to-treat (ITT) population. The per protocol (PP) population includes all randomized participants without protocol deviations.

Analysis dataset 1 is defined as the data from the 16-week period for all randomized participants and does not include extension period data. The 12-week post-randomization period in the biofeedback arm starts on the date of the first biofeedback session. Data lock for the evaluation of efficacy endpoints can be performed upon the completion of this dataset.

The safety data set includes all participants exposed to the biofeedback device.

Primary endpoint analysis

Analysis of the study endpoints will be performed in the ITT (all randomized subjects) and PP populations.

The primary endpoint variable is migraine days. The operational definition used for the analysis will be prespecified in the SAP.

The planned analysis strategy involves a mixed logistic regression model which will include all available daily eDiary entries. The mixed logistic regression model will be used to estimate the difference in the change from baseline in the mean number of migraine days per 28-day period between the treatment and waitlist groups. The model will include the presence or absence of migraine on each day from the baseline and 12-weeks post randomization periods as a dependent binary variable, treatment allocation, time period (baseline, week 1-4, week 5-8 and week 9-12) and an interaction term between treatment allocation and post-randomisation time-periods are included as categorical fixed effects, together with the stratification variable (concomitant preventive medication use). The patient ID will be included as a random effect. The site of inclusion will also be assessed as a potential random effect prior to the unblinding of the statistician to the treatment allocation. The model does not require explicit imputation, as mixed models yield unbiased estimates under the assumption that data are missing at random. This assumption will be assessed and sensitivity analyses considered if warranted.

The primary effect estimate will be the model-based estimates of the difference in change from baseline in mean monthly migraine days between the treatment and waitlist groups, presented with a 95% confidence interval.

Baseline variables that are considered to be highly predictive of outcomes will be discussed and identified a priori and described in the SAP. These variables will be included in multivariate analysis. The SAP will also detail the analysis strategies for the secondary outcomes. Post hoc stratified analyses by sex (women vs. men) and assessment of sex interaction will be conducted.

The statistical analysis plan includes predefined sensitivity analyses, restricting the primary analysis to the per-protocol set and, if feasible, subgroup analyses according to adherence status. Specifically: •

Participants in the interventional group with >90% biofeedback adherence in all three 28-day periods will be compared with the remaining participants in the interventional arm with lower adherence.

Safety data

Safety objectives will be assessed by collecting data on treatment-emergent adverse events encountered during biofeedback training, including adverse events (AEs), serious adverse events (SAEs), adverse device effects (ADEs), serious adverse device effects (SADEs), and unanticipated SADEs (USADEs), and by evaluating the frequency and severity of these occurrences.

All data on treatment-emergent adverse events, ADEs, SADEs, and USADEs will be categorized and summarized. The frequency and severity of treatment-emergent AEs, ADEs, SADEs, and USADEs will be summarized for all enrolled participants and the entire duration of the intervention. Adverse events occurring more than once in individual participants will also be summarized and presented descriptively.

The results of this trial will be published in peer-reviewed international scientific journals. The aim is for results to be made available and spread widely to the public, general practitioners, neurologists, and other health professionals who treat patients with headache. The results will be communicated to patients through relevant channels, such as social media, patient organizations, journals for popular science, and appropriate events and conferences.

Study start 01.01.2023.

This study is conducted in accordance with the principles of ISO 14155:2020 (Clinical Investigation of Medical Devices in Human Subjects), Good Clinical practice, and the Guidelines of the International Headache Society. The study was approved by the Regional Committees for Medical Research Ethics (REK, approval number 502734. Date of approval 2022-10-14) and the Norwegian Medical Product Agency (NOMA) (reference number 22/17254-5. Date of approval 2022-09-01) prior to initiation. Substantial protocol amendments will be reviewed by competent authorities before implementation. Data protection follows the GDPR. We adhere to the Declaration of Helsinki.

To ensure that all subjects have similar opportunities to benefit from enrolment, participants randomized to the waitlist group are offered treatment following the conclusion of the waitlist period. Consent was collected by the investigator conducting the screening visit. Study information was sent in advance of visit 1 by email, scripted study information is provided orally, and any questions are addressed during visit 1 prior to signing to ensure that consent is obtained in all cases. Consent was collected by a digital signature via the national electronic data entry application («Helsenorge»). Study personnel are prohibited from recruiting patients for whom they were directly responsible for treatment.