Ignite Creation Date:
2024-05-06 @ 8:19 PM
Last Modification Date:
2024-10-26 @ 3:25 PM
Study NCT ID:
NCT06333353
Status:
RECRUITING
Last Update Posted:
2024-04-15
First Post:
2024-03-20
Brief Title:
Is Repetitive Transcranial Magnetic Stimulation Effective in Reducing Endometriosis-associated Pain
Sponsor:
University of Ottawa
Organization:
University of Ottawa
Study Overview
Official Title:
Is Repetitive Transcranial Magnetic Stimulation Effective in Reducing Endometriosis-associated Pain A Randomized Controlled Trial
Status:
RECRUITING
Status Verified Date:
2024-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 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
1 to evaluate the effectiveness of an rTMS intervention for pain reduction among those with recalcitrant post-operative EAP
2 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
3 to determine if any improvements in pain observed 30 days after an rTMS intervention are retained 6 months later
4 to identify physical and psychosocial mediators that impact the successful reduction of pain among patients with EAP treated using rTMS
5 to describe patients perceptions of and satisfaction with rTMS as an intervention for EAP
The objectives of this trial are
1 to evaluate the effectiveness of an rTMS intervention for pain reduction among those with recalcitrant post-operative EAP
2 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
3 to determine if any improvements in pain observed 30 days after an rTMS intervention are retained 6 months later
4 to identify physical and psychosocial mediators that impact the successful reduction of pain among patients with EAP treated using rTMS
5 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 1111 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 AB provides realsham rTMS only one investigator who will have no direct involvement with participants will know which coil provides realsham 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 raceethnicity however efforts will be made to ensure diversity in the sample as the prevalence of endometriosis also appears to be influenced by raceethnicity 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 d062 associated with the short rTMS protocol The rTMS literature suggests that a moderate effect size Cohens d005 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 d02 effect suggested that such an interaction would be detected power 080 with a sample size of n100 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 α005 and adjusting for unequal variances if necessary Where there are significant interaction effects Cohens 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 Cohens 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 raceethnicity and sub-analyses will be performed Where this is not possible descriptive analyses by gender and raceethnicity 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 p015 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 ones 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 n16 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
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 1111 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 AB provides realsham rTMS only one investigator who will have no direct involvement with participants will know which coil provides realsham 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 raceethnicity however efforts will be made to ensure diversity in the sample as the prevalence of endometriosis also appears to be influenced by raceethnicity 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 d062 associated with the short rTMS protocol The rTMS literature suggests that a moderate effect size Cohens d005 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 d02 effect suggested that such an interaction would be detected power 080 with a sample size of n100 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 α005 and adjusting for unequal variances if necessary Where there are significant interaction effects Cohens 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 Cohens 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 raceethnicity and sub-analyses will be performed Where this is not possible descriptive analyses by gender and raceethnicity 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 p015 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 ones 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 n16 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None