Home-based Transcranial Direct Current Stimulation (tDCS) Compared to Duloxetine: Non-inferiority Clinical Trial (FIBROSTIM)

Official title

Home-based Transcranial Direct Current Stimulation (tDCS) Compared to Duloxetine in the Treatment of Fibromyalgia: a Randomized Non-inferiority Clinical Trial (FIBROSTIM)

Overview

Fibromyalgia is characterized by widespread pain, fatigue, non-restorative sleep, and psychocognitive alterations, compromising quality of life and leading to absenteeism and early retirement. Up to 70% of patients discontinue treatment with antidepressants and anticonvulsants due to adverse effects or low efficacy, and more than 30% resort to opioid use. Given the treatment challenges and the scarcity of safe alternatives, there is growing interest in interventions such as transcranial direct current stimulation (tDCS), which has shown efficacy in improving symptoms and functionality, with low cost and few side effects. In this context, we designed a randomized, double-blind, double-dummy clinical trial to compare the non-inferiority of 28 home-based anodal tDCS (2 mA) applied over the primary motor cortex (M1) versus duloxetine 60 mg. Both treatments will be combined with physical exercise and pain education. Outcomes will be assessed through multidimensional measures of pain, functionality, global impression of improvement, and the function of the descending pain inhibitory system. Secondary outcomes include quality of life, depressive symptoms, psychophysical pain measures, and treatment adherence. An additional analysis will compare the results of sham tDCS and duloxetine placebo within the non-inferiority model. Predictors of treatment response will also be explored, including symptom severity and oscillatory patterns of cortical electrical activity, rest-activity rhythm, and autonomic function assessed by R-R interval. Furthermore, serum levels of S100-B protein, brain-derived neurotrophic factor (BDNF), and genetic variants related to neuroplasticity in the BDNF Val66Met, Catechol-O-Methyltransferase (COMT) (rs4680) (G\>A), OPRM1, and PER2 genes will be analyzed. Inflammatory markers (TNF-α, IL-1, IL-2, IL-6, IL-10, C-reactive protein) and serum endorphins will also be assessed. A total of 610 women with fibromyalgia (aged 18 to 75 years) will be randomized into three groups (2:2:1): duloxetine + sham tDCS (n=244); active tDCS + placebo (n=244); and sham tDCS + placebo (n=122). Participants will be assessed during treatment and at 3, 6, and 12 months after completing the intervention protocol. An interim analysis will be conducted when \~50% of participants (n ≈ 305) complete the 3-month follow-up by an independent, blinded Data Monitoring Committee (DMC). (i) The trial may be stopped if the conditional probability of demonstrating non-inferiority is \<10%, based on frequentist or Bayesian methods. (i) The trial will be stopped if serious adverse events (SAEs) in the active tDCS group increase by ≥30% compared to duloxetine (p \< 0.01, adjusted). (ii) Early stopping for efficacy will be considered if active tDCS demonstrates clear non-inferiority or superiority over duloxetine on the primary outcome. Superiority requires: (iii) a clinically relevant difference exceeding the non-inferiority margin (≥10% pain reduction); (ii) statistical significance (p \< 0.005, O'Brien-Fleming adjusted); and (iii) a ≥2-point (20%) improvement on the BPI, confirmed in the ITT analysis. This study aims to generate evidence to support the decision-making process of the National Committee for Health Technology Incorporation (CONITEC) regarding the availability of tDCS in the Brazilian Unified Health System (SUS). In addition, identifying predictors of response to tDCS and duloxetine, through the integration of genetic, neurophysiological, inflammatory, and psychosocial markers using machine learning algorithms, will allow for identifying factors that can personalize fibromyalgia treatment. This approach enhances clinical efficacy, reduces costs associated with ineffective interventions, and supports more accurate therapeutic decisions, expanding access to safe, effective, and sustainable care within the public healthcare system

Interventions

• Device Transcranial direct current stimulation (tDCS) plus placebo.
  Participants will be randomized to receive 28 sessions of active anodal tDCS (2 mA) or sham, with the anode over the left M1 and the cathode over the right supraorbital area, for 20 minutes, combined with pain neuroscience education and physical exercises. Sessions will be self-administered at home, daily for 4 weeks. Electrodes (35 cm²) will be placed using neoprene caps (sizes S to XL), adjusted according to head circumference. Monitoring: the device records session time, duration, and adheren
• Drug Duloxetine (60 mg) once daily
  Duloxetine (30 mg and 60 mg) will be purchased from a commercial pharmacy and fractionated by a compounding pharmacy, which will also prepare the placebo. Capsules will be transferred into standardized jars based on dosing schedule: * Jar 01 (white cap): 7 capsules of 30 mg * Jar 02 (green cap): 16 capsules of 60 mg * Jar 03 (green cap): 42 capsules of 60 mg * Jar 04 (white cap): 7 capsules of 30 mg Placebo and duloxetine capsules will be identical in appearance. Kits will be labeled with CAEE
• Device Home-based transcranial direct current stimulation
  Participants will be randomized to receive 28 sessions of active anodal tDCS (2 mA) anode over the left M1 and the cathode over the right supraorbital area, for 20 minutes
• Drug Duloxetine 60 mg
  Duloxetine (30 mg and 60 mg) will be purchased from a commercial pharmacy and fractionated by a compounding pharmacy, which will also prepare the placebo. Capsules will be transferred into standardized jars based on dosing schedule: * Jar 01 (white cap): 7 capsules of 30 mg * Jar 02 (green cap): 16 capsules of 60 mg * Jar 03 (green cap): 42 capsules of 60 mg * Jar 04 (white cap): 7 capsules of 30 mg Placebo and duloxetine capsules will be identical in appearance. Kits will be labeled with CAEE

Primary outcome measures

• Evaluation of Pain Interference [Time frame: Participants will undergo weekly home-based assessments during both the run-in period (Weeks 1 to 3) and the treatment phase (Weeks 4 to 7), as well as at 3, 6, and 12 months after the end of the intervention]
• Patient Global Impression of Improvement [Time frame: To be assessed at Visit 4, after completing the four-week treatment with either active (a-tDCS), s-tDCS), or duloxetine]
• Impact of fibromyalgia symptoms on quality of life [Time frame: Participants will be assessed at Visit 1 (prior to the run-in period), at Visit 4 (after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine), and again at 3, 6, and 12 months following the end of the treatment.]
• Cognitive symptoms [Time frame: Participants will be assessed at Visit 1 (before the run-in period), at Visit 4 (after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine), and again at 3, 6, and 12 months after the end of the treatment.]
• Function of the descending pain inhibitory system [Time frame: Participants will be assessed at Visit 1 (before the run-in period) and at Visit 4 (after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine).]
• Cortical Electrical Activity [Time frame: Participants will be assessed at Visit 1 (before the run-in period) and at Visit 4 (after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine).]

Secondary outcome measures (12)

• Depressive Symptoms [Time frame: Assessment timepoints: Baseline; Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine); 3 months post-treatment; 6 months post-treatment; 12 months post-treatment.]
• Subjective Sleep Quality [Time frame: Assessment timepoints: Baseline; Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine); 3 months post-treatment; 6 months post-treatment; 12 months post-treatment.]
• Circadian Profile (Chronotype) [Time frame: Assessment timepoints: Baseline; Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine); 3 months post-treatment; 6 months post-treatment; 12 months post-treatment.]
• Objective Sleep and Activity (Actigraphy) [Time frame: Actigraph use during the run-in period (Weeks 1 to 3) and throughout the treatment phase (weeks 4 to 7)]
• Analgesic Use [Time frame: Analgesic use during the run-in period (Weeks 1 to 3) and throughout the treatment phase (Weeks 4 to 7).]
• Functional Capacity [Time frame: Assessment timepoints: Baseline; Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine); 3 months post-treatment; 6 months post-treatment; 12 months post-treatment.]
• Heat Pain Threshold [Time frame: Assessment timepoints: Baseline; Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine)]
• Pressure Pain Threshold [Time frame: Assessment timepoints: Baseline; Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine)]
• Cold Pressor Test Pain Intensity [Time frame: Assessment timepoints: Baseline; Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine)]
• Patient-Defined Goals [Time frame: Assessment timepoints: Baseline; Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine)]
• Treatment Adherence [Time frame: Assessment timepoints: Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine)]
• Side Effects [Time frame: Assessment timepoints: During the run-in period (Weeks 1 to 3) and throughout the treatment phase (Weeks 4 to 7).]

Eligibility criteria

Eligibility Criteria

Inclusion criteria

• Woman aged between 18 and 75 years
• Right-handed
• Literate in reading and writing
• Clinical diagnosis of fibromyalgia based on the American College of Rheumatology (ACR) 2010-2016 criteria
• Numeric Pain Scale (NPS) score ≥ 4 on most days in the past 30 days
• Agree no changes in medication dosage during the treatment period (except for analgesics)
• Able to swallow tablets
• Able to understand instructions for using tDCS at home

Exclusion criteria

• Living more than 250 km from Porto Alegre
• Pregnancy
• Decompensated systemic diseases
• Chronic inflammatory rheumatologic diseases
• Untreated hypothyroidism
• Active cancer under treatment
• Alcohol or drug abuse in the past 6 months
• Decompensated psychiatric disorders with suicide risk and a defined plan
• Use of duloxetine at a dose > 60 mg/day
• Metal implants in the brain
• Implanted brain medical devices
• Cardiac pacemaker
• Cochlear implant
• Neurological disorders
• History of traumatic brain injury or neurosurgery

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Factorial

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Brazil · 1 center

• Hospital de Clínicas de Porto Alegre — Porto Alegre

Publications

• Yousefi Soorani L, Shafiei Bafti B, Homam SM, Abbasloo Z, Taghizadeh Zanooghi H. Hypogene enrichment in Miduk porphyry copper ore deposit, Iran. Sci Rep. 2022 Nov 9;12(1):19133. doi: 10.1038/s41598-022-23501-5. PMID 36352022
• Jornada MND, Antunes LC, Alves C, Torres ILS, Fregni F, S Sanches PR, P Silva D Jr, Caumo W. Impact of multiple-session home-based transcranial direct current stimulation (M-HB-tDCS) on eating behavior in fibromyalgia: A factorial randomized clinical trial. Brain Stimul. 2024 Mar-Apr;17(2):152-162. doi: 10.1016/j.brs.2024.02.001. Epub 2024 Feb 8. PMID 38336340
• Fregni F, El-Hagrassy MM, Pacheco-Barrios K, Carvalho S, Leite J, Simis M, Brunelin J, Nakamura-Palacios EM, Marangolo P, Venkatasubramanian G, San-Juan D, Caumo W, Bikson M, Brunoni AR; Neuromodulation Center Working Group. Evidence-Based Guidelines and Secondary Meta-Analysis for the Use of Transcranial Direct Current Stimulation in Neurological and Psychiatric Disorders. Int J Neuropsychopharma PMID 32710772
• Caumo W, Lopes Ramos R, Vicuna Serrano P, da Silveira Alves CF, Medeiros L, Ramalho L, Tomeddi R, Bruck S, Boher L, Sanches PRS, Silva DP Jr, Ls Torres I, Fregni F. Efficacy of Home-Based Transcranial Direct Current Stimulation Over the Primary Motor Cortex and Dorsolateral Prefrontal Cortex in the Disability Due to Pain in Fibromyalgia: A Factorial Sham-Randomized Clinical Study. J Pain. 2024 Feb PMID 37689323
• Caumo W, Deitos A, Carvalho S, Leite J, Carvalho F, Dussan-Sarria JA, Lopes Tarrago Mda G, Souza A, Torres IL, Fregni F. Motor Cortex Excitability and BDNF Levels in Chronic Musculoskeletal Pain According to Structural Pathology. Front Hum Neurosci. 2016 Jul 15;10:357. doi: 10.3389/fnhum.2016.00357. eCollection 2016. PMID 27471458
• Caumo W, Alves RL, Vicuna P, Alves CFDS, Ramalho L, Sanches PRS, Silva DP, da Silva Torres IL, Fregni F. Impact of Bifrontal Home-Based Transcranial Direct Current Stimulation in Pain Catastrophizing and Disability due to Pain in Fibromyalgia: A Randomized, Double-Blind Sham-Controlled Study. J Pain. 2022 Apr;23(4):641-656. doi: 10.1016/j.jpain.2021.11.002. Epub 2021 Nov 13. PMID 34785366
• Brietzke AP, Zortea M, Carvalho F, Sanches PRS, Silva DPJ, Torres ILDS, Fregni F, Caumo W. Large Treatment Effect With Extended Home-Based Transcranial Direct Current Stimulation Over Dorsolateral Prefrontal Cortex in Fibromyalgia: A Proof of Concept Sham-Randomized Clinical Study. J Pain. 2020 Jan-Feb;21(1-2):212-224. doi: 10.1016/j.jpain.2019.06.013. Epub 2019 Jul 26. PMID 31356985

Identifiers

NCT: NCT07203339 · 85778525.8.0000.5327

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗