EndometriosisNCT06333353
Is Repetitive Transcranial Magnetic Stimulation Effective in Reducing Endometriosis-associated Pain
A study testing Real RepetitiveTranscranial Magnetic Stimulation 5 sessions and Real RepetitiveTranscranial Magnetic Stimulation 10 sessions in people with Endometriosis and Pain, run by University of Ottawa at 1 site in Canada.
Trial summary
The goal of this research is to improve pain outcomes for the over 500K Canadian women, girls and gender-diverse individuals who are newly diagnosed with endometriosis each year. Chronic pain that persists after interventions for endometriosis is a huge problem. Read more about this study
- Who is it for?
- Ages 18 to 60 years, women only
- Conditions the study is for
- Endometriosis, Pain
- What is being tested?
- Real RepetitiveTranscranial Magnetic Stimulation 5 sessions and Real RepetitiveTranscranial Magnetic Stimulation 10 sessions
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 152 participants
- Where
- 1 siteCanada
- Study dates
- 12 Apr 2024to 20 Jun 2027
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- Women only
- No healthy volunteers
- Adult
Who may be able to join
- -self-reported endometriosis-associated pain (> 3 in the numeric rating scale, 0-10) that has persisted following medical or surgical intervention,
Who cannot join
- Contra-indications to rTMS (e.g., metal/implants around the head/neck, pacemaker), history of epilepsy (history of seizures) in the family
- Pain symptoms initiated by other known causes (e.g., infections, thyroid disease, autoimmune diseases, gastrointestinal disease)
- Experience a more severe, extra-pelvic pain than that associated with endometriosis
- Pregnancy
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Canada1 site, 1 recruiting
- Recruiting
McLean Function Measurement Lab
Ottawa, Ontario, K1S1S2
Anne-Marie MacDonald, MSc, 613-562-5800 ext. 4102, mfmlab@uottawa.ca
Linda McLean, PhD, 613-562-5800 ext. 4102, lmclea2@uottawa.ca
About this study
Official title: Is Repetitive Transcranial Magnetic Stimulation Effective in Reducing Endometriosis-associated Pain: A Randomized Controlled Trial
The goal of this research is to improve pain outcomes for the over 500K Canadian women, girls and gender-diverse individuals who are newly diagnosed with endometriosis each year. Chronic pain that persists after interventions for endometriosis is a huge problem. There is some evidence that endometriosis-associated pain (EAP) is, at least to some extent, associated with changes in pain physiology, particularly central sensitization of pain. There is currently no effective evidence-informed intervention that addresses EAP. Yet a recent feasibility trial on a repetitive transcranial magnetic stimulation (rTMS) intervention demonstrated promising results compared to a sham intervention for reducing pain in a sample with EAP.
The objectives of this trial are:
- to evaluate the effectiveness of an rTMS intervention for pain reduction among those with recalcitrant post-operative EAP,
- to inform on the utility of a long (10 session) vs short (5 session) protocol for pain reduction among those with recalcitrant post-operative EAP
- to determine if any improvements in pain observed 30 days after an rTMS intervention are retained 6 months later
- to identify physical and psychosocial mediators that impact the successful reduction of pain among patients with EAP treated using rTMS.
- to describe patients' perceptions of and satisfaction with rTMS as an intervention for EAP.
Read the detailed description
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.
Target Sample size: The target sample size is 152 participants (38 per group). The sample size was estimated based on findings of a prospective cohort study by Pinot-Monange et al. which suggested that 75% of participants (9 of 12) will be improved on the PGIC, and that there will be a reduction in reported pain sensitivity (d=0.62) associated with the short rTMS protocol. The rTMS literature suggests that a moderate effect size (Cohen's d=0.05), will be achieved, suggesting that a sample of 30 per group will provide sufficient power to detect an intervention effect. A simulation in R based on 100 replications using a small (d=0.2) effect suggested that such an interaction would be detected (power = 0.80) with a sample size of n=100 (25 per group). The sample size includes estimated conservative drop-out rates, 15%, at the primary end point, and 25% after 6 months.
Recruitment sources: Recruitment will be from a broad range of sources within the Ottawa, Ontario and Gatineau Quebec regions of Canada, including local gynecology clinics, local physiotherapy clinics, social media platforms (Instagram, X, Facebook), printed posters at sites within the community related to social interests, cultural practices, and religious beliefs, and sexual health resource centers.
Planned analyses: Baseline participant characteristics will be aggregated by group and summarized using descriptive statistics. Intent-to-treat analyses will be performed to address Objectives 1-3. To answer Objectives 1 and 2, and to address relevant secondary objectives, 2-way repeated-measures ANOVAs will be performed for continuous variables, including intervention (2 levels: real, sham) and duration (2 levels: short, long) as main effects, and the interaction between intervention and duration, using α=0.05 and adjusting for unequal variances if necessary. Where there are significant interaction effects, Cohen's d and marginal means will be used to estimate effect sizes. Where no significant interactions are found, within- and between-group main effects will be estimated using Cohen's d. Chi-Square analyses will be used to evaluate group differences in the proportion of participants reporting meaningful clinical changes in pain based on the average daily pain (>30% improvement) and the PGIC (somewhat to very much improved), generating Odds Ratios and estimating the number needed to treat with 95% confidence. Analyses after the 6- month follow-up will include time as a main effect. Wherever possible, the data will be disaggregated by gender and race/ethnicity, and sub-analyses will be performed. Where this is not possible, descriptive analyses by gender and race/ethnicity will be reported, highlighting observations that may inform future studies.
To address Objective 4, univariate analyses using only data from those who received real rTMS will be used to identify trends (p<0.15) in baseline and demographic data such as, age, race, gender, daily pain, EHP-30, BPI, Central Sensitization Inventory (CSI), Pain Catastrophizing Scale (PCS), BDI, State Trait Anxiety Inventory (STAI), pressure pain threshold (PPThresh), pressure pain tolerance (PPTol), temporal summation of pain (TS), conditioned pain modulation (CPM) and Tampon Test, suggestive of differences between successes (>30% improvement) and failures. Separate binary logistic regression models will examine the relationship between independent variables tending to differ by group and clinically relevant improvements in dependent variables [PGIC (somewhat to very much improved), daily pain (>30% improved), BPI (> 30% improved) and EHP-30(> 30% improved). Only three predictors will be included in the final model- the one's with the largest effect sizes in univariate testing. Bootstrapping (X1000) will be used to improve the robustness of the models.
Recruitment rate, adherence, adverse events and use of rescue medications (reported on the BPI) will be analyzed descriptively, and any protocol deviations will be described. Post-intervention interview data will be coded, and a thematic analysis will be completed in duplicate using N-Vivo software. Interviews will continue until 15 have been completed, thematic saturation is reached, and no new themes emerge after three consecutive interviews.
Planned Interim analyses: One interim analysis will be performed once n=16 per group have reached the primary endpoint and based on Question 1. The trial will be deemed futile if the conditional power to detect a treatment effect for all intervention groups is <30%. The trial will not be deemed futile based on the power of the interaction effect.
- Conditions
- Endometriosis, Pain
- Being tested
- Real RepetitiveTranscranial Magnetic Stimulation 5 sessions, Sham RepetitiveTranscranial Magnetic Stimulation 5 sessions, Real RepetitiveTranscranial Magnetic Stimulation 10 sessions, Sham RepetitiveTranscranial Magnetic Stimulation 10 sessions
- Keywords
- Repetitive Transcranial Magnetic Stimulation, intervention, endometriosis, pain
- Medical subject headings
- Endometriosis, Pain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Real RepetitiveTranscranial Magnetic Stimulation 5 sessionsDevice
5 consecutive treatment sessions will be provided using a protocol based on the updated guideline (Lefaucheur, 2014) and on Pinot-Monange et al. (2019). Each treatment session will last approximately 30 minutes.
Acceptability, adverse events and side effects will be recorded after each session, while the researchers will also record the total treatment time, difficulties encountered during implementation, and any modifications to the intervention.
Sham RepetitiveTranscranial Magnetic Stimulation 5 sessionsDevice
5 consecutive sham treatment sessions will be provided using a protocol based on the updated guideline (Lefaucheur, 2014) and on Pinot-Monange et al. (2019). Each treatment session will last approximately 30 minutes.
Acceptability, adverse events and side effects will be recorded after each session, while the researchers will also record the total treatment time, difficulties encountered during implementation, and any modifications to the intervention
Real RepetitiveTranscranial Magnetic Stimulation 10 sessionsDevice
10 consective treatment sessions will be provided using a protocol based on the updated guideline (Lefaucheur, 2014) and on Pinot-Monange et al. (2019). Each treatment session will last approximatly 30 minutes.
Acceptability, adverse events and side effects will be recorded after each session, while the researchers will also record the total treatment time, difficulties encountered during implementation, and any modifications to the intervention.
Sham RepetitiveTranscranial Magnetic Stimulation 10 sessionsDevice
10 consective sham treatment sessions will be provided using a protocol based on the updated guideline (Lefaucheur, 2014) and on Pinot-Monange et al. (2019). Each treatment session will last approximatly 30 minutes.
Acceptability, adverse events and side effects will be recorded after each session, while the researchers will also record the total treatment time, difficulties encountered during implementation, and any modifications to the intervention.
| Study group | Role | What they receive |
|---|---|---|
| Real RepetitiveTranscranial Magnetic Stimulation (rTMS) 5 sessions | Experimental | The real rTMS intervention will be delivered to the primary motor cortex (M1) on the left side, over the hand representation, using high frequency (HF) rTMS applied by way of a Magstim Rapid² system. The coil position and orientation will be standardized between treatment visits through using a Brainsight neuronavigation system (Rogue Research, Canada). Each of 5 rTMS sessions will consist of a total of 1500 pulses: 15 sets of pulses delivered at 10Hz for 10s at 80% resting motor threshold (RMT), separated by 50s intervals. The real rTMS intervention will be delivered daily over 5 consecutive days. Receives: Device: Real RepetitiveTranscranial Magnetic Stimulation 5 sessions |
| Sham RepetitiveTranscranial Magnetic Stimulation (rTMS) 5 sessions | Sham comparator | The sham rTMS intervention will be delivered to the primary motor cortex (M1) on the left side, over the hand representation, using high frequency (HF) rTMS applied by way of a Magstim Rapid² system interfaced with a placebo coil, whose position and orientation will standardized between treatment visits using a Brainsight neuronavigation system (Rogue Research, Canada) The sham 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. Each of 5 sham rTMS sessions will consist of a total of 1500 sham pulses: 15 sets of sham pulses (0% output) delivered at 10Hz for 10s, separated by 50s intervals. The sham intervention will be delivered daily over 5 consecutive days. Receives: Device: Sham RepetitiveTranscranial Magnetic Stimulation 5 sessions |
| Real RepetitiveTranscranial Magnetic Stimulation (rTMS) 10 sessions | Experimental | The real 10-session rTMS intervention will be the same as that delivered for the real 5-session rTMS intervention, but delivered as 5 daily sessions, a two day break, and 5 more daily sessions. Receives: Device: Real RepetitiveTranscranial Magnetic Stimulation 10 sessions |
| Sham RepetitiveTranscranial Magnetic Stimulation (rTMS) 10 sessions | Sham comparator | The sham 10 session rTMS intervention will be delivered identically to the sham 5 session intervention, but delivered as 5 daily sessions, a two day break, and 5 more daily sessions. Receives: Device: Sham RepetitiveTranscranial Magnetic Stimulation 10 sessions |
What is being measured
The primary outcome is the main question the study is designed to answer.
Numeric rating scale (NRS) used to record daily pain over 30 days
Pain intensity, using a numeric rating scale (NRS), will be recorded daily for 30 days prior to trial entry to provide a suitable baseline,
It will measure the average and worst overall pain intensity, menstrual and sexual activity related pain (if applicable).
The questions will be applied as described below:
Please rate any pain you experienced today (over the past 24 hours) that you attribute to your endometriosis using a scale from 0 (no pain) to 10 (worst pain imaginable).
Is today your first day of menstrual cycle?
Did you attempt any sexual activity or tampon insertion in the last 24hs? Please rate the pain associated with this activity on a scale from 0 (no pain) to 10 (worst pain imaginable),for sexual activity and/or tampon insertion (if applicable).
Measured: Baseline -30 days after enrolment and before allocation
Numeric rating scale(NRS) used to record daily pain over 30 days
Pain intensity, using a numeric rating scale (NRS), will be recorded daily after the intervention period for 30 days.
It will measure the average and worst overall pain intensity, menstrual and sexual activity related pain (if applicable).
The questions will be applied as described below:
Please rate any pain you experienced today (over the past 24 hours) that you attribute to your endometriosis using a scale from 0 (no pain) to 10 (worst pain imaginable).
Is today your first day of menstrual cycle?
Did you attempt any sexual activity or tampon insertion in the last 24hs? Please rate the pain associated with this activity on a scale from 0 (no pain) to 10 (worst pain imaginable), for sexual activity and/or tampon insertion (if applicable).
Measured: 30 days following intervention
Patient Global Impression of Change (PGIC) in pain
PGIC is a single question through which participants provide a ordinal rating based on their overall perception of change in their pain attributed to the intervention:
Very Much Better, Much Better, Somewhat better, About the same, somewhat worse, much worse, very much worse
Measured: After the Intervention on the final intervention day
Patient Global Impression of Change (PGIC) in pain
PGIC is a single question through which participants provide a ordinal rating based on their overall perception of change in their pain attributed to the intervention:
Very Much Better, Much Better, Somewhat better, About the same, somewhat worse, much worse, very much worse
Measured: 30 days after completing the intervention
Patient Global Impression of Change (PGIC) in pain
PGIC is a single question through which participants provide a ordinal rating based on their overall perception of change in their pain attributed to the intervention:
Very Much Better, Much Better, Somewhat better, About the same, somewhat worse, much worse, very much worse
Measured: 6 months after the intervention
Secondary outcomes (29)
The Beck Depression Inventory (BDI-II)
The 21-item self-administered survey is scored on a scale of 0-3 in a list of four statements arranged in increasing severity about a symptom of depression. BDI-II assesses presence and intensity of mood symptoms. The scale can be divided into 2 subscales, affective symptoms (8 items) and somatic symptoms (13 items). Cut-off scores are available to classify degree of mood intensity.
There is a four-point scale for each item ranging from 0 to 3. On two items (16 and 18) there are seven options to indicate either an increase or decrease of appetite and sleep. Cut-off score guidelines for the BDI-II are given with the recommendation that thresholds be adjusted based on the characteristics of the sample, and the purpose for use of the BDI-II. Total score of 0-13 is considered minimal range, 14-19 is mild, 20-28 is moderate, and 29-63 is severe. This scale can be scored either manually or using the Pearson proprietary software Q-global.
Measured: Baseline
The Beck Depression Inventory (BDI-II)
The 21-item self-administered survey is scored on a scale of 0-3 in a list of four statements arranged in increasing severity about a symptom of depression. BDI-II assesses presence and intensity of mood symptoms. The scale can be divided into 2 subscales, affective symptoms (8 items) and somatic symptoms (13 items). Cut-off scores are available to classify degree of mood intensity.
There is a four-point scale for each item ranging from 0 to 3. On two items (16 and 18) there are seven options to indicate either an increase or decrease of appetite and sleep. Cut-off score guidelines for the BDI-II are given with the recommendation that thresholds be adjusted based on the characteristics of the sample, and the purpose for use of the BDI-II. Total score of 0-13 is considered minimal range, 14-19 is mild, 20-28 is moderate, and 29-63 is severe. This scale can be scored either manually or using the Pearson proprietary software Q-global.
Measured: 30 days following the intervention
The Beck Depression Inventory (BDI-II)
The 21-item self-administered survey is scored on a scale of 0-3 in a list of four statements arranged in increasing severity about a symptom of depression. BDI-II assesses presence and intensity of mood symptoms. The scale can be divided into 2 subscales, affective symptoms (8 items) and somatic symptoms (13 items). Cut-off scores are available to classify degree of mood intensity.
There is a four-point scale for each item ranging from 0 to 3. On two items (16 and 18) there are seven options to indicate either an increase or decrease of appetite and sleep. Cut-off score guidelines for the BDI-II are given with the recommendation that thresholds be adjusted based on the characteristics of the sample, and the purpose for use of the BDI-II. Total score of 0-13 is considered minimal range, 14-19 is mild, 20-28 is moderate, and 29-63 is severe. This scale can be scored either manually or using the Pearson proprietary software Q-global.
Measured: 6 months following the intervention
The State-Trait Anxiety Inventory (STAI)
The State-Trait Anxiety Inventory (STAI) (Stauder, 2003) allows discrimination between anxiety as a personality trait (STAI-T) or as an emotional response to a situation (STAI-S). This 40-item scale has shown a good reliability, consistency, and responsiveness (Sepulcri, 2009). Using the STAI, Sepulcri \& do Amaral (Sepulcri, 2009) reported that 87.5% of patients with EAP reported anxiety, with significant associations between both STAI-T and STAI-S and pain intensity.
Total scores for state and trait are calculated, ranging from 20 - 80. Higher scores indicate greater anxiety.
- = Scores between 20-39 means "no or low anxiety"
- = Scores between 40-59 means "moderate anxiety"
- = Scores between 60-80 means "high anxiety"
Measured: Baseline
The Pain Catastrophizing Scale
This is a reliable and valid scale to measure of catastrophizing. The scores from this questionnaire is predictors of intensity of physical and emotional distress. It is a self-report measure, consisting of 13 items scored from 0 to 4, resulting in a total possible score of 52. The higher the score, the more catastrophizing thoughts are present.
Measured: Baseline
The Central sensitization index
The Central Sensitisation Inventory (CSI) is a self-report outcome measure designed to identify patients who have symptoms that may be related to central sensitisation (CS) or central sensitivity syndromes (CSS). Part A includes 25 questions related to common CSS symptoms.
Part B determines if the patient has been diagnosed with certain CSS disorders or related disorders, such as anxiety and depression. CSI severity levels have been established for part A: subclinical = 0 to 29; mild = 30 to 39; moderate = 40 to 49; severe = 50 to 59; and extreme = 60 to 100.
Measured: Baseline
Female Sexual Distress Scale (FSDS)
The Female Sexual Distress Scale-Revised (FSDS-R) is a 13-item questionnaire designed to assess sexually related distress in women with hypoactive sexual desire disorder (HSDD). It has been validated for evaluating distress associated with inadequate or impaired sexual function.
The total score on the FSDS-R ranges from 0 to 48, with higher scores indicating higher levels of sexual distress. A cutoff score of 15 or more is recommended for determining the presence of personal sexual distress.
Measured: Baseline
Adherence to the intervention protocol
Attendance of rTMS treatment visits will be tracked (%).
Measured: During intervention sessions
Pressure pain threshold (PPThresh)
PPT will be determined using an algometer device in three regions over the lower abdomen [lower left and right quadrants (4cm medial to the anterior superior iliac spine) and midline (1 cm superior to the midline pubic symphysis)]. Three sites remote to the pelvis (right thenar eminence, right upper trapezius, and right medial gastrocnemius) will also be assessed.
PPT will be defined as the median pressure (Newton), among three trials, at which participants first report pain.
After each pressure application participants will be asked to rate their pain using the NRS from 0 to 10.
Measured: Baseline before allocation
Pressure pain threshold (PPThresh)
PPT will be determined using an algometer device in three regions over the lower abdomen [lower left and right quadrants (4cm medial to the anterior superior iliac spine) and midline (1 cm superior to the midline pubic symphysis)]. Three sites remote to the pelvis (right thenar eminence, right upper trapezius, and right medial gastrocnemius) will also be assessed.
PPT will be defined as the median pressure (Newton), among three trials, at which participants first report pain.
After each pressure application participants will be asked to rate their pain using the NRS from 0 to 10.
Measured: After the final intervention session on the same day as that session
Pressure Pain Tolerance (PPTol)
PPTol will be determined using an algometer device in three regions over the lower abdomen [lower left and right quadrants (4cm medial to the anterior superior iliac spine) and midline (1 cm superior to the midline pubic symphysis)]. Three sites remote to the pelvis (right thenar eminence, right upper trapezius, and right medial gastrocnemius) will also be assessed.
PPTol will be defined as the median pressure (Newton), among three trials, at which participants can tolerate the pressure before the sensation becomes intolerable or unbearable.
After each pressure application participants will be asked to rate their pain in a numerical rating scale (NRS) from 0 to 10.
Measured: Baseline before allocation
Pressure Pain Tolerance (PPTol)
PPTol will be determined using an algometer device in three regions over the lower abdomen [lower left and right quadrants (4cm medial to the anterior superior iliac spine) and midline (1 cm superior to the midline pubic symphysis)]. Three sites remote to the pelvis (right thenar eminence, right upper trapezius, and right medial gastrocnemius) will also be assessed.
PPTol will be defined as the median pressure (Newton), among three trials, at which participants can tolerate the pressure before the sensation becomes intolerable or unbearable.
After each pressure application participants will be asked to rate their pain in a numerical rating scale (NRS) from 0 to 10.
Measured: Immediately after the final intervention session
Perceived pain intensity (PPI)
Perceived pain intensity (PPI) will be applied, using an algometer device during 5 seconds using the mean pressure between PPThresh and PPTol obtained previously for each participant, in all sites described above. After each pressure application participants will be asked to rate their pain in a numerical rating scale (NRS) from 0 to 10.
Measured: Baseline before allocation
Perceived pain intensity (PPI)
Perceived pain intensity (PPI) will be applied, using an algometer device during 5 seconds using the mean pressure between PPThresh and PPTol obtained previously for each participant, in all sites described above. After each pressure application participants will be asked to rate their pain in a numerical rating scale (NRS) from 0 to 10.
Measured: Immediately after the final intervention session
Temporal summation (TS) of pain
TS is reflective of sensitization through peripheral and/or central mechanisms. The stimulus intensity will be the PPI determined above at the midline lower abdominal site and at the thenar site, determined during pressure pain threshold (PPT) assessment. Ten stimuli will be delivered at each site at a rate of one per second. Pain intensity reported using a NRS, induced by the application of the stimulus on the 1st and 10th application will be recorded. TS will be considered as a dichotomous variable, deemed to be present if there is a positive difference > 1 between NRS ratings on the tenth minus that of the first application of the stimulus and negative otherwise
Measured: Baseline before allocation
Temporal summation (TS) of pain
TS is reflective of sensitization through peripheral and/or central mechanisms. The stimulus intensity will be the PPI at the lower abdominal site and at the thenar site, determined during pressure pain threshold (PPT) assessment. Ten stimuli will be delivered at each site at a rate of one per second. Pain intensity reported using a NRS, induced by the application of the stimulus on the 1st and 10th application will be recorded. TS will be considered as a dichotomous variable, deemed to be present if there is a positive difference > 1 between NRS ratings on the tenth minus that of the first application of the stimulus and negative otherwise
Measured: Immediately after the final intervention session
Pain rating during the tampon test
The participants will be provided with Original Regular Tampax Tampon and will be instructed to insert and then remove it. After, they will be asked to record the degree of pain during the entire insertion/removal experience in a 11-point numerical rating scale (NRS) with anchors of 0 (no pain at all) to 10 (worst pain imaginable).
Measured: Baseline before allocation
Pain rating during the tampon test
The participants will be provided with Original Regular Tampax Tampon and will be instructed to insert and then remove it. After, they will be asked to record the degree of pain during the entire insertion/removal experience in a 11-point numerical rating scale (NRS) with anchors of 0 (no pain at all) to 10 (worst pain imaginable).
Measured: Immediately after the final intervention session
Conditioned pain modulation (CPM)
CPM is manifested by a reduction in pain perception in one location through the simultaneous application of a painful stimulus at a distant, non-segmental location on the body. A lack of CPM is reflective of decreased descending endogenous pain inhibition, a contributor to central sensitization.
Through the PPThresh (test stimulus) will be tested at the lower midline abdominal site and the thenar eminence site. A blood pressure cuff will be applied to the dominant upper arm and inflated at a rate of 20 mmHg/s until the participant reports a pain intensity of 3/10 (conditioning stimulus). The test stimulus will be repeated 3X at each site while the pressure is retained at the upper arm. CPM will be deemed present if the median PPThresh is lower with the conditioning stimulus applied than prior to the conditioning stimulus.
Measured: Baseline before allocation
Conditioned pain modulation (CPM)
CPM is manifested by a reduction in pain perception in one location through the simultaneous application of a painful stimulus at a distant, non-segmental location on the body. A lack of CPM is reflective of decreased descending endogenous pain inhibition, a contributor to central sensitization.
Through the PPThresh (test stimulus) will be tested at the lower midline abdominal site and the thenar eminence site. A blood pressure cuff will be applied to the dominant upper arm and inflated at a rate of 20 mmHg/s until the participant reports a pain intensity of 3/10 (conditioning stimulus). The test stimulus will be repeated 3X at each site while the pressure is retained at the upper arm. CPM will be deemed present if the median PPThresh is lower with the conditioning stimulus applied than prior to the conditioning stimulus.
Measured: Immediately after the final intervention session
The Brief Pain Inventory
It evaluates a patient's pain experience over the previous 1 weeks through locating the pain, noting medication or other interventions, and 11 different numeric rating scales (NRSs) ask about pain intensity (current, least, most, and average for the past 24 hours) and the effect of the pain on function during various activities of daily living. The BPI is an excellent tool for monitoring the effect of pain or treatment of pain, or both, in terms of a patient's functional ability or disability over time. Cronbach alpha reliability ranges from 0.77 to 0.91.
Scoring: The short version of the BPI (Short form) includes 9 items. It uses a 0 to 10 numeric rating scales for item rating.
Pain Score:
- 1 - 4 = Mild Pain
- 5 - 6 = Moderate Pain
- 7 - 10 = Severe Pain
Measured: Baseline before allocation
The Brief Pain Inventory
It evaluates a patient's pain experience over the previous 7 days through locating the pain, noting medication or other interventions, and 11 different numeric rating scales (NRSs) ask about pain intensity (current, least, most, and average for the past 24 hours) and the effect of the pain on function during various activities of daily living. The BPI is an excellent tool for monitoring the effect of pain or treatment of pain, or both, in terms of a patient's functional ability or disability over time. Cronbach alpha reliability ranges from 0.77 to 0.91.
Scoring: The short version of the BPI (Short form) includes 9 items. It uses a 0 to 10 numeric rating scales for item rating.
Pain Score:
- 1 - 4 = Mild Pain
- 5 - 6 = Moderate Pain
- 7 - 10 = Severe Pain
Measured: 30 days after the final intervention session
The Brief Pain Inventory
It evaluates a patient's pain experience over the previous 1 weeks through locating the pain, noting medication or other interventions, and 11 different numeric rating scales (NRSs) ask about pain intensity (current, least, most, and average for the past 24 hours) and the effect of the pain on function during various activities of daily living. The BPI is an excellent tool for monitoring the effect of pain or treatment of pain, or both, in terms of a patient's functional ability or disability over time. Cronbach alpha reliability ranges from 0.77 to 0.91.
Scoring: The short version of the BPI (Short form) includes 9 items. It uses a 0 to 10 numeric rating scales for item rating.
Pain Score:
- 1 - 4 = Mild Pain
- 5 - 6 = Moderate Pain
- 7 - 10 = Severe Pain
Measured: 6 months after the final intervention session
The Endometriosis Health Profile Questionnaire (EPH-30)
The 30 questions of the EHP-30 involve five scales (pain, control and powerlessness, emotional well-being, social support, and self-image) answered based on a 4-week recall period. Higher scores (/100) reflect better health.
Measured: Baseline before allocation
The Endometriosis Health Profile Questionnaire (EPH-30)
The 30 questions of the EHP-30 involve five scales (pain, control and powerlessness, emotional well-being, social support, and self-image) answered based on a 4-week recall period. Higher scores (/100) reflect better health.
Measured: 30 days after the final intervention session
The Endometriosis Health Profile Questionnaire (EPH-30)
The 30 questions of the EHP-30 involve five scales (pain, control and powerlessness, emotional well-being, social support, and self-image) answered based on a 4-week recall period. Higher scores (/100) reflect better health.
Measured: 6 months after the final intervention session
Patient satisfaction with treatment (PST)
Global patient satisfaction with treatment is a single question through which participants provide their rating of satisfaction using a scale from zero to ten. Higher ratings reflect greater satisfaction.
Measured: Immediately after the intervention on the final day of the intervention
Patient satisfaction with treatment (PST)
Global patient satisfaction with treatment is a single question through which participants provide their rating of satisfaction using a scale from zero to ten. Higher ratings reflect greater satisfaction.
Measured: 30 days after the final intervention session
Patient satisfaction with treatment (PST)
Global patient satisfaction with treatment is a single question through which participants provide their rating of satisfaction using a scale from zero to ten. Higher ratings reflect greater satisfaction.
Measured: 6 months after the final intervention session
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Mar 2024
- Study start12 Apr 2024
- Primary completion20 May 2027 (estimated)
- Study completion20 Jun 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (25)Papers the sponsor has linked to this study.
- Other trials for EndometriosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Parallel Assignment
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 152 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Ottawa
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Dr. Linda McLean, University of Ottawa
- Investigators
- Linda McLean, PhD, Principal investigator, University of Ottawa
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06333353
- Sponsor's protocol ID
- H-06-23-9278
- Status last verified
- Apr 2024
- First submitted
- 20 Mar 2024
- Last updated
- 15 Apr 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Spreadsheets will be provide by email upon request and based on the planned use of the data
Publications
Bajaj P, Bajaj P, Madsen H, Arendt-Nielsen L. Endometriosis is associated with central sensitization: a psychophysical controlled study. J Pain. 2003 Sep;4(7):372-80. doi: 10.1016/s1526-5900(03)00720-x.
PubMed 14622679Gatchel RJ, Peng YB, Peters ML, Fuchs PN, Turk DC. The biopsychosocial approach to chronic pain: scientific advances and future directions. Psychol Bull. 2007 Jul;133(4):581-624. doi: 10.1037/0033-2909.133.4.581.
PubMed 17592957Kennedy DL, Kemp HI, Ridout D, Yarnitsky D, Rice ASC. Reliability of conditioned pain modulation: a systematic review. Pain. 2016 Nov;157(11):2410-2419. doi: 10.1097/j.pain.0000000000000689.
PubMed 27559835O'Connell NE, Marston L, Spencer S, DeSouza LH, Wand BM. Non-invasive brain stimulation techniques for chronic pain. Cochrane Database Syst Rev. 2018 Mar 16;3(3):CD008208. doi: 10.1002/14651858.CD008208.pub4.
PubMed 29547226Singh S, Soliman AM, Rahal Y, Robert C, Defoy I, Nisbet P, Leyland N. Prevalence, Symptomatic Burden, and Diagnosis of Endometriosis in Canada: Cross-Sectional Survey of 30 000 Women. J Obstet Gynaecol Can. 2020 Jul;42(7):829-838. doi: 10.1016/j.jogc.2019.10.038. Epub 2020 Jan 27.
PubMed 32001176McNamara HC, Frawley HC, Donoghue JF, Readman E, Healey M, Ellett L, Reddington C, Hicks LJ, Harlow K, Rogers PAW, Cheng C. Peripheral, Central, and Cross Sensitization in Endometriosis-Associated Pain and Comorbid Pain Syndromes. Front Reprod Health. 2021 Sep 1;3:729642. doi: 10.3389/frph.2021.729642. eCollection 2021.
PubMed 36303969Carey ET, Martin CE, Siedhoff MT, Bair ED, As-Sanie S. Biopsychosocial correlates of persistent postsurgical pain in women with endometriosis. Int J Gynaecol Obstet. 2014 Feb;124(2):169-73. doi: 10.1016/j.ijgo.2013.07.033. Epub 2013 Oct 31.
PubMed 24290537Coccia ME, Rizzello F, Palagiano A, Scarselli G. Long-term follow-up after laparoscopic treatment for endometriosis: multivariate analysis of predictive factors for recurrence of endometriotic lesions and pain. Eur J Obstet Gynecol Reprod Biol. 2011 Jul;157(1):78-83. doi: 10.1016/j.ejogrb.2011.02.008. Epub 2011 Apr 9.
PubMed 21481523Pagano RL, Fonoff ET, Dale CS, Ballester G, Teixeira MJ, Britto LRG. Motor cortex stimulation inhibits thalamic sensory neurons and enhances activity of PAG neurons: possible pathways for antinociception. Pain. 2012 Dec;153(12):2359-2369. doi: 10.1016/j.pain.2012.08.002. Epub 2012 Sep 25.
PubMed 23017297Leung A, Donohue M, Xu R, Lee R, Lefaucheur JP, Khedr EM, Saitoh Y, Andre-Obadia N, Rollnik J, Wallace M, Chen R. rTMS for suppressing neuropathic pain: a meta-analysis. J Pain. 2009 Dec;10(12):1205-16. doi: 10.1016/j.jpain.2009.03.010. Epub 2009 May 23.
PubMed 19464959Pinot-Monange A, Moisset X, Chauvet P, Gremeau AS, Comptour A, Canis M, Pereira B, Bourdel N. Repetitive Transcranial Magnetic Stimulation Therapy (rTMS) for Endometriosis Patients with Refractory Pelvic Chronic Pain: A Pilot Study. J Clin Med. 2019 Apr 13;8(4):508. doi: 10.3390/jcm8040508.
PubMed 31013910Turk DC, Dworkin RH, Burke LB, Gershon R, Rothman M, Scott J, Allen RR, Atkinson HJ, Chandler J, Cleeland C, Cowan P, Dimitrova R, Dionne R, Farrar JT, Haythornthwaite JA, Hertz S, Jadad AR, Jensen MP, Kellstein D, Kerns RD, Manning DC, Martin S, Max MB, McDermott MP, McGrath P, Moulin DE, Nurmikko T, Quessy S, Raja S, Rappaport BA, Rauschkolb C, Robinson JP, Royal MA, Simon L, Stauffer JW, Stucki G, Tollett J, von Stein T, Wallace MS, Wernicke J, White RE, Williams AC, Witter J, Wyrwich KW. Developing patient-reported outcome measures for pain clinical trials: IMMPACT recommendations. Pain. 2006 Dec 5;125(3):208-215. doi: 10.1016/j.pain.2006.09.028. Epub 2006 Oct 25. No abstract available.
PubMed 17069973Neelakantan D, Omojole F, Clark TJ, Gupta JK, Khan KS. Quality of life instruments in studies of chronic pelvic pain: a systematic review. J Obstet Gynaecol. 2004 Nov;24(8):851-8. doi: 10.1080/01443610400019138.
PubMed 16147635Jones G, Kennedy S, Barnard A, Wong J, Jenkinson C. Development of an endometriosis quality-of-life instrument: The Endometriosis Health Profile-30. Obstet Gynecol. 2001 Aug;98(2):258-64. doi: 10.1016/s0029-7844(01)01433-8.
PubMed 11506842Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singap. 1994 Mar;23(2):129-38.
PubMed 8080219
Study at a glance
From the registry record, last updated by the sponsor on 15 Apr 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Is Repetitive Transcranial Magnetic Stimulation Effective in Reducing Endometriosis-associated Pain: A Randomized Controlled Trial
- ClinicalTrials.gov ID
- NCT06333353
- Acronym / sponsor ID
- H-06-23-9278
- Conditions
- Endometriosis, Pain
- Keywords
- Repetitive Transcranial Magnetic Stimulation, intervention, endometriosis, pain
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 152 participants (estimated)
- Lead sponsor
- University of OttawaUniversity, hospital or other
- Study start
- 12 Apr 2024 (actual)
- Primary completion
- 20 May 2027 (estimated)
- Study completion
- 20 Jun 2027 (estimated)
- First posted
- 27 Mar 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The goal of this research is to improve pain outcomes for the over 500K Canadian women, girls and gender-diverse individuals who are newly diagnosed with endometriosis each year. Chronic pain that persists after interventions for endometriosis is a huge problem. There is some evidence that endometriosis-associated pain (EAP) is, at least to some extent, associated with changes in pain physiology, particularly central sensitization of pain. There is currently no effective evidence-informed intervention that addresses EAP. Yet a recent feasibility trial on a repetitive transcranial magnetic stimulation (rTMS) intervention demonstrated promising results compared to a sham intervention for reducing pain in a sample with EAP.
The objectives of this trial are:
- to evaluate the effectiveness of an rTMS intervention for pain reduction among those with recalcitrant post-operative EAP,
- to inform on the utility of a long (10 session) vs short (5 session) protocol for pain reduction among those with recalcitrant post-operative EAP
- to determine if any improvements in pain observed 30 days after an rTMS intervention are retained 6 months later
- to identify physical and psychosocial mediators that impact the successful reduction of pain among patients with EAP treated using rTMS.
- to describe patients' perceptions of and satisfaction with rTMS as an intervention for EAP.
Detailed description
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.
Target Sample size: The target sample size is 152 participants (38 per group). The sample size was estimated based on findings of a prospective cohort study by Pinot-Monange et al. which suggested that 75% of participants (9 of 12) will be improved on the PGIC, and that there will be a reduction in reported pain sensitivity (d=0.62) associated with the short rTMS protocol. The rTMS literature suggests that a moderate effect size (Cohen's d=0.05), will be achieved, suggesting that a sample of 30 per group will provide sufficient power to detect an intervention effect. A simulation in R based on 100 replications using a small (d=0.2) effect suggested that such an interaction would be detected (power = 0.80) with a sample size of n=100 (25 per group). The sample size includes estimated conservative drop-out rates, 15%, at the primary end point, and 25% after 6 months.
Recruitment sources: Recruitment will be from a broad range of sources within the Ottawa, Ontario and Gatineau Quebec regions of Canada, including local gynecology clinics, local physiotherapy clinics, social media platforms (Instagram, X, Facebook), printed posters at sites within the community related to social interests, cultural practices, and religious beliefs, and sexual health resource centers.
Planned analyses: Baseline participant characteristics will be aggregated by group and summarized using descriptive statistics. Intent-to-treat analyses will be performed to address Objectives 1-3. To answer Objectives 1 and 2, and to address relevant secondary objectives, 2-way repeated-measures ANOVAs will be performed for continuous variables, including intervention (2 levels: real, sham) and duration (2 levels: short, long) as main effects, and the interaction between intervention and duration, using α=0.05 and adjusting for unequal variances if necessary. Where there are significant interaction effects, Cohen's d and marginal means will be used to estimate effect sizes. Where no significant interactions are found, within- and between-group main effects will be estimated using Cohen's d. Chi-Square analyses will be used to evaluate group differences in the proportion of participants reporting meaningful clinical changes in pain based on the average daily pain (>30% improvement) and the PGIC (somewhat to very much improved), generating Odds Ratios and estimating the number needed to treat with 95% confidence. Analyses after the 6- month follow-up will include time as a main effect. Wherever possible, the data will be disaggregated by gender and race/ethnicity, and sub-analyses will be performed. Where this is not possible, descriptive analyses by gender and race/ethnicity will be reported, highlighting observations that may inform future studies.
To address Objective 4, univariate analyses using only data from those who received real rTMS will be used to identify trends (p<0.15) in baseline and demographic data such as, age, race, gender, daily pain, EHP-30, BPI, Central Sensitization Inventory (CSI), Pain Catastrophizing Scale (PCS), BDI, State Trait Anxiety Inventory (STAI), pressure pain threshold (PPThresh), pressure pain tolerance (PPTol), temporal summation of pain (TS), conditioned pain modulation (CPM) and Tampon Test, suggestive of differences between successes (>30% improvement) and failures. Separate binary logistic regression models will examine the relationship between independent variables tending to differ by group and clinically relevant improvements in dependent variables [PGIC (somewhat to very much improved), daily pain (>30% improved), BPI (> 30% improved) and EHP-30(> 30% improved). Only three predictors will be included in the final model- the one's with the largest effect sizes in univariate testing. Bootstrapping (X1000) will be used to improve the robustness of the models.
Recruitment rate, adherence, adverse events and use of rescue medications (reported on the BPI) will be analyzed descriptively, and any protocol deviations will be described. Post-intervention interview data will be coded, and a thematic analysis will be completed in duplicate using N-Vivo software. Interviews will continue until 15 have been completed, thematic saturation is reached, and no new themes emerge after three consecutive interviews.
Planned Interim analyses: One interim analysis will be performed once n=16 per group have reached the primary endpoint and based on Question 1. The trial will be deemed futile if the conditional power to detect a treatment effect for all intervention groups is <30%. The trial will not be deemed futile based on the power of the interaction effect.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 4
- Model description
- Parallel Assignment
| Arm | Type | Receives |
|---|---|---|
| Real RepetitiveTranscranial Magnetic Stimulation (rTMS) 5 sessions | Experimental | Device: Real RepetitiveTranscranial Magnetic Stimulation 5 sessionsThe real rTMS intervention will be delivered to the primary motor cortex (M1) on the left side, over the hand representation, using high frequency (HF) rTMS applied by way of a Magstim Rapid² system. The coil position and orientation will be standardized between treatment visits through using a Brainsight neuronavigation system (Rogue Research, Canada). Each of 5 rTMS sessions will consist of a total of 1500 pulses: 15 sets of pulses delivered at 10Hz for 10s at 80% resting motor threshold (RMT), separated by 50s intervals. The real rTMS intervention will be delivered daily over 5 consecutive days. |
| Sham RepetitiveTranscranial Magnetic Stimulation (rTMS) 5 sessions | Sham comparator | Device: Sham RepetitiveTranscranial Magnetic Stimulation 5 sessionsThe sham rTMS intervention will be delivered to the primary motor cortex (M1) on the left side, over the hand representation, using high frequency (HF) rTMS applied by way of a Magstim Rapid² system interfaced with a placebo coil, whose position and orientation will standardized between treatment visits using a Brainsight neuronavigation system (Rogue Research, Canada) The sham 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. Each of 5 sham rTMS sessions will consist of a total of 1500 sham pulses: 15 sets of sham pulses (0% output) delivered at 10Hz for 10s, separated by 50s intervals. The sham intervention will be delivered daily over 5 consecutive days. |
| Real RepetitiveTranscranial Magnetic Stimulation (rTMS) 10 sessions | Experimental | Device: Real RepetitiveTranscranial Magnetic Stimulation 10 sessionsThe real 10-session rTMS intervention will be the same as that delivered for the real 5-session rTMS intervention, but delivered as 5 daily sessions, a two day break, and 5 more daily sessions. |
| Sham RepetitiveTranscranial Magnetic Stimulation (rTMS) 10 sessions | Sham comparator | Device: Sham RepetitiveTranscranial Magnetic Stimulation 10 sessionsThe sham 10 session rTMS intervention will be delivered identically to the sham 5 session intervention, but delivered as 5 daily sessions, a two day break, and 5 more daily sessions. |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (1 listed)
- -self-reported endometriosis-associated pain (> 3 in the numeric rating scale, 0-10) that has persisted following medical or surgical intervention,
Key exclusion criteria (4 listed)
- Contra-indications to rTMS (e.g., metal/implants around the head/neck, pacemaker), history of epilepsy (history of seizures) in the family
- Pain symptoms initiated by other known causes (e.g., infections, thyroid disease, autoimmune diseases, gastrointestinal disease)
- Experience a more severe, extra-pelvic pain than that associated with endometriosis
- Pregnancy
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Real RepetitiveTranscranial Magnetic Stimulation 5 sessions5 consecutive treatment sessions will be provided using a protocol based on the updated guideline (Lefaucheur, 2014) and on Pinot-Monange et al. (2019). Each treatment session will last approximately 30 minutes. Acceptability, adverse events and side effects will be recorded after each session, while the researchers will also record the total treatment time, difficulties encountered during implementation, and any modifications to the intervention. | Device | Real RepetitiveTranscranial Magnetic Stimulation (rTMS) 5 sessions |
| Sham RepetitiveTranscranial Magnetic Stimulation 5 sessions5 consecutive sham treatment sessions will be provided using a protocol based on the updated guideline (Lefaucheur, 2014) and on Pinot-Monange et al. (2019). Each treatment session will last approximately 30 minutes. Acceptability, adverse events and side effects will be recorded after each session, while the researchers will also record the total treatment time, difficulties encountered during implementation, and any modifications to the intervention | Device | Sham RepetitiveTranscranial Magnetic Stimulation (rTMS) 5 sessions |
| Real RepetitiveTranscranial Magnetic Stimulation 10 sessions10 consective treatment sessions will be provided using a protocol based on the updated guideline (Lefaucheur, 2014) and on Pinot-Monange et al. (2019). Each treatment session will last approximatly 30 minutes. Acceptability, adverse events and side effects will be recorded after each session, while the researchers will also record the total treatment time, difficulties encountered during implementation, and any modifications to the intervention. | Device | Real RepetitiveTranscranial Magnetic Stimulation (rTMS) 10 sessions |
| Sham RepetitiveTranscranial Magnetic Stimulation 10 sessions10 consective sham treatment sessions will be provided using a protocol based on the updated guideline (Lefaucheur, 2014) and on Pinot-Monange et al. (2019). Each treatment session will last approximatly 30 minutes. Acceptability, adverse events and side effects will be recorded after each session, while the researchers will also record the total treatment time, difficulties encountered during implementation, and any modifications to the intervention. | Device | Sham RepetitiveTranscranial Magnetic Stimulation (rTMS) 10 sessions |
Primary outcome
Numeric rating scale (NRS) used to record daily pain over 30 days
Time frame: Baseline -30 days after enrolment and before allocation
Pain intensity, using a numeric rating scale (NRS), will be recorded daily for 30 days prior to trial entry to provide a suitable baseline, It will measure the average and worst overall pain intensity, menstrual and sexual activity related pain (if applicable). The questions will be applied as described below: Please rate any pain you experienced today (over the past 24 hours) that you attribute to your endometriosis using a scale from 0 (no pain) to 10 (worst pain imaginable). Is today your first day of menstrual cycle? Did you attempt any sexual activity or tampon insertion in the last 24hs? Please rate the pain associated with this activity on a scale from 0 (no pain) to 10 (worst pain imaginable),for sexual activity and/or tampon insertion (if applicable).
Numeric rating scale(NRS) used to record daily pain over 30 days
Time frame: 30 days following intervention
Pain intensity, using a numeric rating scale (NRS), will be recorded daily after the intervention period for 30 days. It will measure the average and worst overall pain intensity, menstrual and sexual activity related pain (if applicable). The questions will be applied as described below: Please rate any pain you experienced today (over the past 24 hours) that you attribute to your endometriosis using a scale from 0 (no pain) to 10 (worst pain imaginable). Is today your first day of menstrual cycle? Did you attempt any sexual activity or tampon insertion in the last 24hs? Please rate the pain associated with this activity on a scale from 0 (no pain) to 10 (worst pain imaginable), for sexual activity and/or tampon insertion (if applicable).
Patient Global Impression of Change (PGIC) in pain
Time frame: After the Intervention on the final intervention day
PGIC is a single question through which participants provide a ordinal rating based on their overall perception of change in their pain attributed to the intervention: Very Much Better, Much Better, Somewhat better, About the same, somewhat worse, much worse, very much worse
Patient Global Impression of Change (PGIC) in pain
Time frame: 30 days after completing the intervention
PGIC is a single question through which participants provide a ordinal rating based on their overall perception of change in their pain attributed to the intervention: Very Much Better, Much Better, Somewhat better, About the same, somewhat worse, much worse, very much worse
Patient Global Impression of Change (PGIC) in pain
Time frame: 6 months after the intervention
PGIC is a single question through which participants provide a ordinal rating based on their overall perception of change in their pain attributed to the intervention: Very Much Better, Much Better, Somewhat better, About the same, somewhat worse, much worse, very much worse
29 secondary outcomes
The Beck Depression Inventory (BDI-II)
Time frame: Baseline
The Beck Depression Inventory (BDI-II)
Time frame: 30 days following the intervention
The Beck Depression Inventory (BDI-II)
Time frame: 6 months following the intervention
The State-Trait Anxiety Inventory (STAI)
Time frame: Baseline
The Pain Catastrophizing Scale
Time frame: Baseline
The Central sensitization index
Time frame: Baseline
Female Sexual Distress Scale (FSDS)
Time frame: Baseline
Adherence to the intervention protocol
Time frame: During intervention sessions
Pressure pain threshold (PPThresh)
Time frame: Baseline before allocation
Pressure pain threshold (PPThresh)
Time frame: After the final intervention session on the same day as that session
Pressure Pain Tolerance (PPTol)
Time frame: Baseline before allocation
Pressure Pain Tolerance (PPTol)
Time frame: Immediately after the final intervention session
Perceived pain intensity (PPI)
Time frame: Baseline before allocation
Perceived pain intensity (PPI)
Time frame: Immediately after the final intervention session
Temporal summation (TS) of pain
Time frame: Baseline before allocation
Temporal summation (TS) of pain
Time frame: Immediately after the final intervention session
Pain rating during the tampon test
Time frame: Baseline before allocation
Pain rating during the tampon test
Time frame: Immediately after the final intervention session
Conditioned pain modulation (CPM)
Time frame: Baseline before allocation
Conditioned pain modulation (CPM)
Time frame: Immediately after the final intervention session
The Brief Pain Inventory
Time frame: Baseline before allocation
The Brief Pain Inventory
Time frame: 30 days after the final intervention session
The Brief Pain Inventory
Time frame: 6 months after the final intervention session
The Endometriosis Health Profile Questionnaire (EPH-30)
Time frame: Baseline before allocation
The Endometriosis Health Profile Questionnaire (EPH-30)
Time frame: 30 days after the final intervention session
The Endometriosis Health Profile Questionnaire (EPH-30)
Time frame: 6 months after the final intervention session
Patient satisfaction with treatment (PST)
Time frame: Immediately after the intervention on the final day of the intervention
Patient satisfaction with treatment (PST)
Time frame: 30 days after the final intervention session
Patient satisfaction with treatment (PST)
Time frame: 6 months after the final intervention session
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Apr 2024.
- Background: PubMed 14622679Bajaj P, Bajaj P, Madsen H, Arendt-Nielsen L. Endometriosis is associated with central sensitization: a psychophysical controlled study. J Pain. 2003 Sep;4(7):372-80. doi: 10.1016/s1526-5900(03)00720-x.
- Background: PubMed 17592957Gatchel RJ, Peng YB, Peters ML, Fuchs PN, Turk DC. The biopsychosocial approach to chronic pain: scientific advances and future directions. Psychol Bull. 2007 Jul;133(4):581-624. doi: 10.1037/0033-2909.133.4.581.
- Background: PubMed 27559835Kennedy DL, Kemp HI, Ridout D, Yarnitsky D, Rice ASC. Reliability of conditioned pain modulation: a systematic review. Pain. 2016 Nov;157(11):2410-2419. doi: 10.1097/j.pain.0000000000000689.
- Background: PubMed 29547226O'Connell NE, Marston L, Spencer S, DeSouza LH, Wand BM. Non-invasive brain stimulation techniques for chronic pain. Cochrane Database Syst Rev. 2018 Mar 16;3(3):CD008208. doi: 10.1002/14651858.CD008208.pub4.
- Background: PubMed 32001176Singh S, Soliman AM, Rahal Y, Robert C, Defoy I, Nisbet P, Leyland N. Prevalence, Symptomatic Burden, and Diagnosis of Endometriosis in Canada: Cross-Sectional Survey of 30 000 Women. J Obstet Gynaecol Can. 2020 Jul;42(7):829-838. doi: 10.1016/j.jogc.2019.10.038. Epub 2020 Jan 27.
- Background: PubMed 36303969McNamara HC, Frawley HC, Donoghue JF, Readman E, Healey M, Ellett L, Reddington C, Hicks LJ, Harlow K, Rogers PAW, Cheng C. Peripheral, Central, and Cross Sensitization in Endometriosis-Associated Pain and Comorbid Pain Syndromes. Front Reprod Health. 2021 Sep 1;3:729642. doi: 10.3389/frph.2021.729642. eCollection 2021.
- Background: PubMed 24290537Carey ET, Martin CE, Siedhoff MT, Bair ED, As-Sanie S. Biopsychosocial correlates of persistent postsurgical pain in women with endometriosis. Int J Gynaecol Obstet. 2014 Feb;124(2):169-73. doi: 10.1016/j.ijgo.2013.07.033. Epub 2013 Oct 31.
- Background: PubMed 21481523Coccia ME, Rizzello F, Palagiano A, Scarselli G. Long-term follow-up after laparoscopic treatment for endometriosis: multivariate analysis of predictive factors for recurrence of endometriotic lesions and pain. Eur J Obstet Gynecol Reprod Biol. 2011 Jul;157(1):78-83. doi: 10.1016/j.ejogrb.2011.02.008. Epub 2011 Apr 9.
- Background: PubMed 23017297Pagano RL, Fonoff ET, Dale CS, Ballester G, Teixeira MJ, Britto LRG. Motor cortex stimulation inhibits thalamic sensory neurons and enhances activity of PAG neurons: possible pathways for antinociception. Pain. 2012 Dec;153(12):2359-2369. doi: 10.1016/j.pain.2012.08.002. Epub 2012 Sep 25.
- Background: PubMed 19464959Leung A, Donohue M, Xu R, Lee R, Lefaucheur JP, Khedr EM, Saitoh Y, Andre-Obadia N, Rollnik J, Wallace M, Chen R. rTMS for suppressing neuropathic pain: a meta-analysis. J Pain. 2009 Dec;10(12):1205-16. doi: 10.1016/j.jpain.2009.03.010. Epub 2009 May 23.
- Background: PubMed 31013910Pinot-Monange A, Moisset X, Chauvet P, Gremeau AS, Comptour A, Canis M, Pereira B, Bourdel N. Repetitive Transcranial Magnetic Stimulation Therapy (rTMS) for Endometriosis Patients with Refractory Pelvic Chronic Pain: A Pilot Study. J Clin Med. 2019 Apr 13;8(4):508. doi: 10.3390/jcm8040508.
- Background: PubMed 17069973Turk DC, Dworkin RH, Burke LB, Gershon R, Rothman M, Scott J, Allen RR, Atkinson HJ, Chandler J, Cleeland C, Cowan P, Dimitrova R, Dionne R, Farrar JT, Haythornthwaite JA, Hertz S, Jadad AR, Jensen MP, Kellstein D, Kerns RD, Manning DC, Martin S, Max MB, McDermott MP, McGrath P, Moulin DE, Nurmikko T, Quessy S, Raja S, Rappaport BA, Rauschkolb C, Robinson JP, Royal MA, Simon L, Stauffer JW, Stucki G, Tollett J, von Stein T, Wallace MS, Wernicke J, White RE, Williams AC, Witter J, Wyrwich KW. Developing patient-reported outcome measures for pain clinical trials: IMMPACT recommendations. Pain. 2006 Dec 5;125(3):208-215. doi: 10.1016/j.pain.2006.09.028. Epub 2006 Oct 25. No abstract available.
- Individual participant dataSharing planned: Yes. Spreadsheets will be provide by email upon request and based on the planned use of the data
Related trials for Endometriosis
Not yet recruiting
Prevalence of Small Intestinal Bacterial Overgrowth (SIBO) in Women With Endometriosis
SIBO, Endometriosis
Recruiting
Endometriosis Transcriptomic Cell Atlas
Endometriosis, Infertility
Not yet recruiting
Psychotherapy in Patients With Endometriosis: Cognitive Behavioral Therapy Versus Acceptance and Commitment Therapy
Endometriosis, Adenomyosis
Not yet recruitingObservational study
Impact of a Diagnosis or Lack of a Diagnosis of Endometriosis Via a Saliva Test on Pain Catastrophizing, Quality of Life, Symptoms of Anxiety and Depression, and Treatment Adherence
Endometriosis
Not yet recruitingPhase 2
PRECISION-E2: Teverelix in Women With Endometriosis - Pharmacodynamics, Safety and Precision Medicine Correlates
Endometriosis Pelvic, Endometriosis Ovaries
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Linda McLean, PhD principal investigator
University of Ottawa
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Real RepetitiveTranscranial Magnetic Stimulation 5 sessions and Real RepetitiveTranscranial Magnetic Stimulation 10 sessions in people with Endometriosis and Pain, run by University of Ottawa at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 15 Apr 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Anne-Marie MacDonald, MSc (613-562-5800 ext. 4102, alake@uottawa.ca), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Numeric rating scale (NRS) used to record daily pain over 30 days (time frame: Baseline -30 days after enrolment and before allocation). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06333353, which also lists 25 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Apr 2024.