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Repetitive Transcranial Magnetic Stimulation of Relief of Fibromyalgia Pain (TMSFFI)

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ClinicalTrials.gov Identifier: NCT03658694
Recruitment Status : Recruiting
First Posted : September 5, 2018
Last Update Posted : December 28, 2020
Sponsor:
Collaborator:
Fundação de Amparo à Pesquisa do Estado de São Paulo
Information provided by (Responsible Party):
Daniel Ciampi Araujo de Andrade, MD, PhD, University of Sao Paulo

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 real rTMS of two different doses (1500 vs 3000 pulses per session) 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.

Condition or disease Intervention/treatment Phase
Fibromyalgia Procedure: rTMS high dose - stage 1 Procedure: rTMS sham - stage 1 Procedure: high dose rTMS - stage 2 Procedure: low dose rTMS - stage 2 Not Applicable

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 real rTMS of two different doses (1500 vs 3000 pulses per session) 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 high-dose rTMS 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 high and low dose rTMS.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

This is an adaptive sequential trial of FM patients. In stage 1 patients were randomly allocated into two parallel arms (rTMS high dose, sham) using adaptive methodology. In stage 2, after the end of the first trial, patients will be allocated to two arms (low dose rTMS, high dose 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 pandemic. We have had dropouts due to a few patients developing covid and also due to patients having fear to become infected while attending hospital visits

Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Repetitive Transcranial Magnetic Stimulation of the Precentral-gyrus in the Relief of Fibromyalgia Pain: an International Multicenter Controlled Adaptative Trial
Actual Study Start Date : April 1, 2019
Estimated Primary Completion Date : September 1, 2021
Estimated Study Completion Date : November 1, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Fibromyalgia

Arm Intervention/treatment
Experimental: rTMS high dose - stage 1
In stage 1 patients were randomly allocated to receive real repetitive transcranial magnetic stimulation.
Procedure: rTMS high dose - stage 1
Patients will be undergoing to transcranial magnetic stimulation session with high dose 3000 pulses

Experimental: rTMS sham - stage 1
In stage 1 patients were randomly allocated to receive sham repetitive transcranial magnetic stimulation.
Procedure: rTMS sham - stage 1
Patients will be undergoing to sham transcranial magnetic stimulation session with high dose 3000 pulses

Experimental: high dose rTMS - stage 2
In stage 2, after the end of the first trial will be allocated to receive high dose of repetitive transcranial magnetic stimulation.
Procedure: high dose rTMS - stage 2
Patients will be undergoing to transcranial magnetic stimulation session with high dose 3000 pulses

Experimental: low dose rTMS - stage 2
In stage 2, after the end of the first trial will be allocated to receive low dose of repetitive transcranial magnetic stimulation.
Procedure: low dose rTMS - stage 2
Patients will be undergoing to transcranial magnetic stimulation session with low dose 1500 pulses




Primary Outcome Measures :
  1. Analgesic effects of motor cortex stimulation [ Time Frame: 8th week of treatment ]
    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.


Secondary Outcome Measures :
  1. Global impression of change [ Time Frame: 8th week of treatment ]
    Assess % of very much and much improved

  2. Pain intensity [ Time Frame: At the end of the induction period (10th day) and 12th week ]
    Measured by VAS (0 no pain -10 worst pain)

  3. Mood [ Time Frame: baseline and 12th week ]
    Assess mood by hospital anxiety and depression scale

  4. Medication use [ Time Frame: baseline and 12th week ]
    Measured by Brief Pain Inventory

  5. Interference in daily activites [ Time Frame: baseline and 12th week ]
    Measured by brief pain inventory

  6. Impact of fibromyalgia daily [ Time Frame: baseline and 12th week ]
    Assess by fibromyalgia impact questionnaire

  7. Phenotypical markers of analgesic response [ Time Frame: baseline and 12th week ]
    Assessment of phenotypical markers of analgesic response

  8. Adverse events [ Time Frame: baseline and 12th week ]
    Assess of adverse events by standardized questionnaire'



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03658694


Contacts
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Contact: Daniel Ciampi de Andrade, MD, PhD +55 11 2661-7152 ciampi@usp.br
Contact: Abrahão Baptista, PhD +55 11 23206270 abrahao.baptista@gmail.com

Locations
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Brazil
Universidade Federal de Pernambuco Recruiting
Recife, Pernambuco, Brazil, 50670-901
Contact: Kátia Monte-Silva, PhD    +55 81 21267579    monte.silvakk@gmail.com   
Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC/FMUSP) Recruiting
São Paulo, SP, Brazil, 05403900
Contact: Daniel Ciampi, PhD    + 55 11 997753538    ciampi@usp.br   
Federal University of ABC Recruiting
São Bernardo Do Campo, Brazil, 09606-070
Contact: Abrahão Fontes Baptista, PhD    +55 11 2320-6270    a.baptista@ufabc.edu.br   
Ambulatório de Fisioterapia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo Recruiting
São Paulo, Brazil, 05403-010
Contact: Clarice Tanaka, PhD    +55 11 2661 6867    cltanaka@usp.br   
France
Centre d'Evaluation et de Traitement de la Douleur Hôpital Ambroise Paré Recruiting
Paris, France, 92100
Contact: Nadine Attal, PhD    +33 1 49 09 5931    nadine.attal@aphp.fr   
Contact: Didier Bouhassira, PhD    +33 1 49 09 5931    didier.bouhassira@inserm.fr   
Japan
Department of Neuromodulation Osaka University Recruiting
Osaka, Japan, 565-0871
Contact: Koich Hosomi, PhD    +81 6 6879 4138    k-hosomi@nsurg.med.osaka-u.ac.jp   
Sponsors and Collaborators
University of Sao Paulo
Fundação de Amparo à Pesquisa do Estado de São Paulo
Investigators
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Principal Investigator: Daniel Ciampi de Andrade, MD, PhD Pain Center, Department of Neurology, University of Sao Paulo, Sao Paulo, Brazil
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Responsible Party: Daniel Ciampi Araujo de Andrade, MD, PhD, Pain Center of Department of Neurology, University of Sao Paulo
ClinicalTrials.gov Identifier: NCT03658694    
Other Study ID Numbers: RGDCA03
First Posted: September 5, 2018    Key Record Dates
Last Update Posted: December 28, 2020
Last Verified: December 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Daniel Ciampi Araujo de Andrade, MD, PhD, University of Sao Paulo:
fibromyalgia
repetitive transcranial magnetic stimulation
Additional relevant MeSH terms:
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Fibromyalgia
Myofascial Pain Syndromes
Muscular Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Neuromuscular Diseases
Nervous System Diseases