Is Repetitive Transcranial Magnetic Stimulation Effective in Reducing Endometriosis-associated Pain: A Randomized Controlled Trial

This will be a double-blind, randomized-controlled trial (RCT) using a 2X2 factorial design. The protocol was developed following the Consolidated Standards of Reporting Trials (CONSORT) statement and also follows the Canadian Institutes for Health Research (CIHR) Strategy for Patient-Oriented Research (SPOR) to adapt research activities and dissemination strategies to patients equitably and effectively.

The interventions include repetitive transcranial magnetic stimulation (rTMS) delivered using either a real or a sham coil and one of two intervention durations (short: 5-session, long: 10 session), thus four study groups with 1:1:1:1 allocation.

Intervention: The rTMS intervention will be delivered to the primary motor cortex (M1) on the left side, over the hand representation using high frequency (HF) rTMS. Since there is no known somatotopy for pelvic pain, handedness is not thought to be important, however, handedness will be recorded to verify this. The rTMS intervention will be applied by way of a Magstim Rapid² system (Whitland, UK) coupled with a 70mm cooled figure-of-8 coil. The coil position and orientation will be standardized between treatment visits through using a Brainsight neuronavigation system (Rogue Research, Canada). A standard Montreal Neurological Institute (MNI) atlas will be used. The stimulation target will be individually defined at baseline as the site eliciting the highest averaged motor evoked potential (MEP) peak-to-peak amplitude in the first dorsal interosseous (FDI) muscle. The resting motor threshold (RMT) will be defined as the lowest intensity stimulus that elicits a MEP in the FDI of the right hand, with a peak-to-peak amplitude of at least 50 uV in 50% of trials. MEPs will be recorded using the on-board EMG system. Each rTMS session (real or sham) will consist of a total of 1500 pulses: 15 sets of pulses delivered at 10Hz for 10s at 80% RMT, separated by 50s intervals. The short protocol will involve interventions on 5 consecutive days, while the long protocol will include a 2-day break and another 5- day intervention. Acceptability, adverse events and side effects will be recorded after each session. Missed visits will be rescheduled wherever possible (but tracked). and adherence will be recorded as a proportion of sessions attended.

Participant allocation: Concealed, computer-generated allocation will be performed using permuted block randomization (block size= 4) only after a participant has consented and completed all questionnaires at baseline. The allocation sequence will be managed by an independent investigator not associated with the project. It will be concealed from the study team through storage in a password protected file on an encrypted computer, backed up in a password-protected directory. Groups will be labelled as A-short, A-long, B-short, B-long, to keep investigators and participants blinded as to which coil (A/B) provides real/sham rTMS (only one investigator who will have no direct involvement with participants will know which coil provides real/sham rTMS; they look, sound and feel identical). Treatment duration will be revealed only to the recruitment officer, to the individual delivering the intervention, and the participant, since they will need to know the length of the protocol to schedule intervention sessions and follow-up. Gender will be recorded and if possible, gender-based sub-analyses will be performed. the sample will not be stratified by race/ethnicity, however efforts will be made to ensure diversity in the sample, as the prevalence of endometriosis also appears to be influenced by race/ethnicity. Recruitment bias will be minimized through using multiple recruitment sources with broad reach. Consistent with the CONSORT extension recommendations for trials involving non-pharmacological interventions, the researchers who perform baseline and follow-up assessments will not be involved in the treatment, and will be blinded to group allocation.

Data collection: A series of questionnaires will be completed using an on-line platform before and after the intervention and laboratory-based assessments will occur on the day of the first and final (5th or 10th) intervention session, at the later of which participants will report their patient global impression of change (PGIC) in pain, and their patient satisfaction with treatment (PST). All participants will be followed daily to record their daily pain (NRS 0-10) in the 30 days before the first and 30 days after the last rTMS intervention session using automated text messaging or e-mail notifications, or phone calls if that is their preference. 30 days after the intervention (primary end point), and 6 months later, participants will provide their PGIC for pain, PST, and complete the Brief Pain inventory (BPI), the Endometriosis Health Profile (EHP-30) and the Beck Depression Index (BDI), through an on-line platform (reminders will be sent and non-completion will be monitored, with follow-up by the protocol officer to ensure completion wherever possible). Individuals randomized to the real intervention (both short and long protocols) will be invited to participate in a semi-structured interview through which we aim to capture a nuanced impression of the effectiveness of the intervention, its acceptability, and other observations.