Clinical trial NCT03658694: Repetitive Transcranial Magnetic Stimulation of Relief of Fibromyalgia Pain
Official title: Repetitive Transcranial Magnetic Stimulation of the Precentral-gyrus in the Relief of Fibromyalgia Pain: an International Multicenter Controlled Adaptative Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Fibromyalgia
Keywords: fibromyalgia
repetitive transcranial magnetic stimulation
Lead sponsor: University of Sao Paulo
Sponsor class: OTHER
Collaborators: name: Fundação de Amparo à Pesquisa do Estado de São Paulo
First posted: 2018-09-05
Enrollment: 80
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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: 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 .

Eligibility criteria: Inclusion Criteria:

1. 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).
2. Age ≥18 years;
3. Be able to understand study protocol and give signed, written informed consent
4. Not under opioids
5. VAS score ≥ 40/100 mm;

Exclusion Criteria:

1. Known abuse of alcohol or illicit drugs
2. Known psychiatric conditions
3. 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);
4. Not being under chronic contraceptive use (intrauterine dispositive or oral contraceptive)
5. Other medical conditions demand hospitalization;
6. Participation in other clinical studies at the same time

Primary outcomes:
measure: Analgesic effects of motor cortex stimulation
timeFrame: 8th week of treatment
Secondary outcomes:
measure: Global impression of change
timeFrame: 8th and 16th weeks of treatment
measure: Pain intensity
timeFrame: At the end of the induction period (10th day) and 16th week
measure: Mood
timeFrame: 8th week of treatment
measure: Impact of fibromyalgia daily
timeFrame: 8th and 16th week of treatment
measure: Interference in daily activites
timeFrame: 8th week of treatment
measure: Medication use
timeFrame: 8th week of treatment
measure: Phenotypical markers of analgesic response
timeFrame: 8th and 16th week of treatment
measure: Adverse events
timeFrame: 8th and 16th week of treatment
Other outcomes:
Locations:
city: Recife
country: Brazil
facility: Universidade Federal de Pernambuco
state: Pernambuco
city: São Paulo
country: Brazil
facility: Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC/FMUSP)
state: SP
city: São Bernardo Do Campo
country: Brazil
facility: Federal University of ABC
city: São Paulo
country: Brazil
facility: Ambulatório de Fisioterapia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo
city: Paris
country: France
facility: Centre d'Evaluation et de Traitement de la Douleur Hôpital Ambroise Paré
city: Osaka
country: Japan
facility: Department of Neuromodulation Osaka University
Study officials:
affiliation: Pain Center, Department of Neurology, University of Sao Paulo, Sao Paulo, Brazil
name: Daniel Ciampi de Andrade, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: