Repetitive Transcranial Magnetic Stimulation of Relief of Fibromyalgia Pain

Study Overview
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Brief Summary
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There are currently several points concerning rTMS for pain relief that have a huge impact in the practical application of rTMS in clinical practice, but which have not been approached by previous studies. Also, an even more important issue is the frequency of the sessions in each treatment protocol. The idea of performing stimulation in chronic pain patients on a consecutive daily basis for long-term treatments seem unrealistic and potentially costly. However, it has been reported in animals, healthy subjects and FM patients that the analgesic effects of rTMS can outlast the stimulation session for several minutes and even days. This has led to the proposal that pain treatment with rTMS could be performed in consecutive daily induction sessions, followed by spaced (weekly, fortnightly and even monthly) maintenance sessions. This approach is similar to what is performed routinely in patients with major depression treated by rTMS to the dorsolateral prefrontal cortex, and has successfully been tested in FM patients in a single- center study. Should this approach prove effective in larger prospective multicentric studies, rTMS could enter the armamentarium of non-invasive, non- pharmacological, low-adverse event therapeutic options to relieve fibromyalgia- related pain and associate symptoms. Hence, our aim is to conduct a multicentric international clinical trial on the influence of rTMS in the control of pain in a consecutive adaptive trial design where conventional rTMS (10Hz) and patterned rTMS (theta-burst) will be studied. Stimulations will be performed in a clinical practice-friendly approach, where daily maintenance sessions will be followed by weekly, and fortnightly stimulation sessions. There have been very scarce adaptive trials in the pain and non-invasive stimulation fields. This methodological approach allows for the use of lower number of patients in consecutive trials and, among other qualities, it allows for the imputation of data from the first trial into the second one, thus decreasing the duration of the studies and the number of participants.

Detailed Description
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There are currently several points concerning rTMS for pain relief that have a huge impact in the practical application of rTMS in clinical practice, but which have not been approached by previous studies. One of them refers to dosing of the treatment. rTMS sessions have been proposed to comprise from 1000 to 3000 pulses of stimulation in each session, which means that treatment sessions may last from 7 to 20 minutes. While there are positive studies reporting different numbers of pulses, the actual stimulation protocol chosen may impact not only the efficacy of the treatment, but also the duration of the stimulation session, the time patients stay at the health-care facility, and, thus, cost and compliance to treatment. Also, an even more important issue is the frequency of the sessions in each treatment protocol. The idea of performing stimulation in chronic pain patients on a consecutive daily basis for long-term treatments seem unrealistic and potentially costly. However, it has been reported in animals, healthy subjects and FM patients that the analgesic effects of rTMS can outlast the stimulation session for several minutes and even days. This has led to the proposal that pain treatment with rTMS could be performed in consecutive daily induction sessions, followed by spaced (weekly, fortnightly and even monthly) maintenance sessions. This approach is similar to what is performed routinely in patients with major depression treated by rTMS to the dorsolateral prefrontal cortex, and has successfully been tested in FM patients in a single- center study. Should this approach prove effective in larger prospective multicentric studies, rTMS could enter the armamentarium of non-invasive, non- pharmacological, low-adverse event therapeutic options to relieve fibromyalgia- related pain and associate symptoms. Hence, our aim is to conduct a multicentric international clinical trial on the influence of rTMS in the control of pain in a consecutive adaptive trial design where conventional rTMS and patterned rTMS will be studied. Stimulations will be performed in a clinical practice-friendly approach, where daily maintenance sessions will be followed by weekly, and fortnightly stimulation sessions. There have been very scarce adaptive trials in the pain and non-invasive stimulation fields. This methodological approach allows for the use of lower number of patients in consecutive trials and, among other qualities, it allows for the imputation of data from the first trial into the second one, thus decreasing the duration of the studies and the number of participants. Similarly, this technical approach allows for pre-planned interim analyses to be performed during data collection, allowing for the sample size to be readjusted during the trial, and, more importantly, allowing for trial termination due to futility or due to achievement of the primary endpoint before the end of the original preplanned data collection period, with lower risk of bias. Here, the adaptive approach will allow one not only to compare conventional rTMS (10Hz) to sham stimulation, but also, on second consecutive study, it will provide the first head-to-head study on rTMS to date comparing the analgesic effects of conventional (10Hz) and patterned (theta-burst) rTMS .

Official Title
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Repetitive Transcranial Magnetic Stimulation of the Precentral-gyrus in the Relief of Fibromyalgia Pain: an International Multicenter Controlled Adaptative Trial

Conditions
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Fibromyalgia

Intervention / Treatment
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* Procedure: Conventional rTMS - study 1
* Procedure: Sham rTMS - study 1
* Procedure: Conventional rTMS - study 2
* Procedure: Patterned rTMS - stage 2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female patients with diagnosis fibromyalgia according to the ACR 2016 criteria (patient satisfies modified 2016 fibromyalgia criteria if the following 3 conditions are met: 1) widespread pain index (WPI) ≥ 7 and symptom severity scale (SSS) score 5 OR WPI of 4-6 and SSS score ≥ 9. 2) Generalized pain, defined as pain in at least 4 of 5 regions, must be present. Jaw, chest, and abdominal pain are not included in generalized pain definition. 3) Symptoms have been generally present for at least 3 months. 4) A diagnosis of fibromyalgia is valid irrespective of other diagnoses. A diagnosis of fibromyalgia does not exclude the presence of other clinically important illnesses). Age ≥18 years; Be able to understand study protocol and give signed, written informed consent Not under opioids VAS score ≥ 40/100 mm; Exclusion Criteria: Known abuse of alcohol or illicit drugs Known psychiatric conditions Contraindications to rTMS (42) (Head trauma or concussion, metal implants in the skull, pregnancy, cardiac pacemaker, medication infusion devices, previous troubles with TMS or MRI); Not being under chronic contraceptive use (intrauterine dispositive or oral contraceptive) Other medical conditions demand hospitalization; Participation in other clinical studies at the same time

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: This is an adaptive sequential trial of FM patients. In stage 1 patients were randomly allocated into two parallel arms (conventional rTMS, sham) using adaptive methodology. In stage 2, after the end of the first trial, patients will be allocated to two arms (conventional rTMS, patterned rTMS). Both stages will be conducted in a sequential methodology where an interim analysis will take place and indicate whether will take place trial is positive and of the scientific board agrees open its start. Recruitment time will be extended by 12 months due to dropouts related to the Covid-19 pandemic. We have had dropouts due to some patients who developed Covid-19 and also due to patients who were afraid of becoming infected during hospital visits. Those patients who dropped out of the study due to the pandemic will be excluded from the main analysis and will be analyzed as a secondary outcome.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Conventional rTMS - study 1<br>In study 1 patients were randomly allocated to receive conventional repetitive transcranial magnetic stimulation (10Hz). | Procedure: Conventional rTMS - study 1<br>* Patients will be undergoing to 10Hz transcranial magnetic stimulation session<br>|
| Experimental: Sham rTMS - study 1<br>In study 1 patients were randomly allocated to receive sham repetitive transcranial magnetic stimulation. | Procedure: Sham rTMS - study 1<br>* Patients will be undergoing to sham transcranial magnetic stimulation session<br>|
| Experimental: Conventional rTMS - study 2<br>In study 2, after the end of the first trial will be allocated to receive conventional of repetitive transcranial magnetic stimulation (10Hz). | Procedure: Conventional rTMS - study 2<br>* Patients will be undergoing to 10Hz transcranial magnetic stimulation session<br>|
| Experimental: Patterned rTMS - study 2<br>In study 2, after the end of the first trial will be allocated to receive patterned of repetitive transcranial magnetic stimulation (Theta-burst). | Procedure: Patterned rTMS - stage 2<br>* Patients will be undergoing to theta-burst transcranial magnetic stimulation session<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Analgesic effects of motor cortex stimulation | Percentage of responders based on the reduction of ≥50% in pain intensity (numerical rating scale 0-10) at the end of the study compared to baseline. | 8th week of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Global impression of change | Assess % of very much and much improved | 8th week of treatment | 
| Pain intensity | Measured by VAS (0 no pain -10 worst pain) | At the end of the induction period (10th day) and 12th week | 
| Mood | Assess mood by hospital anxiety and depression scale | baseline and 12th week | 
| Medication use | Measured by Brief Pain Inventory | baseline and 12th week | 
| Interference in daily activites | Measured by brief pain inventory | baseline and 12th week | 
| Impact of fibromyalgia daily | Assess by fibromyalgia impact questionnaire | baseline and 12th week | 
| Phenotypical markers of analgesic response | Assessment of phenotypical markers of analgesic response | baseline and 12th week | 
| Adverse events | Assess of adverse events by standardized questionnaire' | baseline and 12th week | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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fibromyalgia, repetitive transcranial magnetic stimulation