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

Hospital de Clinicas de Porto Alegre

Status: Enrolling

Conditions: EEG; Fibromyalgia (FM); Duloxetine; BDNF; tDCS

Treatments: Drug: Duloxetine (60 mg) once daily; Drug: Duloxetine 60 mg; Device: Transcranial direct current stimulation (tDCS) plus placebo.; Device: Home-based transcranial direct current stimulation

Study type: Interventional

Funder types: Other

Identifiers

NCT07203339

85778525.8.0000.5327

Details and patient eligibility

About

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

Enrollment: 610 estimated patients

Sex: Female

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Factorial Assignment

Masking: Quadruple Blind

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610 participants in 3 patient groups

(s-tDCS over M1+placebo medication) - Home-Based Transcranial Direct Current Stimulation (tDCS)

Sham Comparator group

Description:

The sham tDCS protocol will use the same electrode montage as the active tDCS, with active current delivered for 30 seconds at the beginning, after 10 minutes, and at the end of the session. The current will be applied using 35 cm² electrodes.

Treatment:

Device: Home-based transcranial direct current stimulation

Device: Transcranial direct current stimulation (tDCS) plus placebo.

The study includes 28 sessions of home-based anodal transcranial direct current stimulation (tDCS)

Experimental group

Description:

Active anodal tDCS (2 mA) or sham tDCS will be applied over the left M1 (anode) and the right supraorbital area (cathode) for 20 minutes, combined with physical exercises and educational guidance on pain neuroscience for fibromyalgia. After in-person training, participants will receive instructions for home use.

Treatment:

Device: Home-based transcranial direct current stimulation

Device: Transcranial direct current stimulation (tDCS) plus placebo.

Duloxetine 60 mg

Active Comparator group

Description:

The pharmacological intervention will use duloxetine (30 mg and 60 mg), commercially acquired. The medication and placebo will be sourced via contracts with a compounding pharmacy and a retail drugstore. Generic Duloxetine Hydrochloride (Germed) will be purchased and sent for fractioning and placebo preparation. Each participant will receive a kit with four jars (duloxetine or placebo): Jar 01 (white lid): 7 × 30 mg - Week 1 (run-in); Jar 02 (green lid): 16 × 60 mg - Weeks 2-3 (run-in); Jar 03 (green lid): 42 × 60 mg - During tDCS; Jar 04 (white lid): 7 × 30 mg - Post-treatment taper.

Treatment:

Drug: Duloxetine 60 mg

Drug: Duloxetine (60 mg) once daily