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

Not Applicable

Not yet recruiting

• Conditions: Fibromyalgia (FM); tDCS; Duloxetine; BDNF; EEG
• Interventions: Device: Transcranial direct current stimulation (tDCS) plus placebo.; Drug: Duloxetine (60 mg) once daily; Device: Home-based transcranial direct current stimulaiton; Drug: Duloxetine 60 mg

• Registration Number: NCT07203339
• Lead Sponsor: Hospital de Clinicas de Porto Alegre

Brief Summary

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

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2025-06-04
• Status Verified: 2025-09
• Study First Submitted QC: 2025-09-24
• Last Update Submitted: 2025-09-24
• Study Start: 2025-09-30
• Study First Posted: 2025-10-02
• Last Update Posted: 2025-10-02
• Primary Completion: 2028-12
• Study Completion: 2028-12-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: Female
• Target Recruitment: 610

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
(s-tDCS over M1+placebo medication) - Home-Based Transcranial Direct Current Stimulation (tDCS)	Transcranial direct current stimulation (tDCS) plus placebo.	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.
(s-tDCS over M1+placebo medication) - Home-Based Transcranial Direct Current Stimulation (tDCS)	Home-based transcranial direct current stimulaiton	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.
The study includes 28 sessions of homebased anodal transcranial direct current stimulation (tDCS)	Transcranial direct current stimulation (tDCS) plus placebo.	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.
The study includes 28 sessions of homebased anodal transcranial direct current stimulation (tDCS)	Home-based transcranial direct current stimulaiton	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.
Duloxetine 60 mg	Duloxetine (60 mg) once daily	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.
Duloxetine 60 mg	Duloxetine 60 mg	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.

Primary Outcome Measures

Name	Time	Method
Cognitive symptoms	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.	Barkley Deficits in Executive Functioning Scale (Short Form).Each item is rated on a Likert scale from 1 (never or rarely) to 4 (very often), resulting in a total score range of 20 to 80, with higher scores indicating greater executive functioning impairment
Function of the descending pain inhibitory system	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).	Conditioned Pain Modulation (CPM) test: This test assesses descending pain inhibition.; This test assesses the efficiency of descending pain inhibitory pathways. Pain intensity is rated using a verbal numerical rating scale (0 = no pain to 10 = worst possible pain) before (T0) and during (T1) cold-water immersion. The CPM effect is calculated as the difference between pain ratings at T0 and T1, with greater reductions indicating more effective pain inhibition.
Evaluation of Pain Interference	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	The Brief Pain Inventory (BPI) assesses pain intensity and interference across seven domains, generating a global interference index using 0-10 scales.
Patient Global Impression of Improvement	To be assessed at Visit 4, after completing the four-week treatment with either active (a-tDCS), s-tDCS), or duloxetine	Patient Global Impression of Improvement (PGI-I): A 7-point scale that assesses the patient's overall perception of change in their condition, ranging from 'very much worse' (1) to 'very much improved' (7). Higher scores indicate greater perceived improvement (e.g., reduced symptoms or better functioning), while lower scores reflect worsening of symptoms or condition.
Impact of fibromyalgia symptoms on quality of life	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.	Fibromyalgia Impact Questionnaire (FIQ): Brazilian version assessing quality of life across function, overall impact, and symptoms. Scores range from 0 to 100, with higher scores indicating greater impact of fibromyalgia on the individual's daily life and functioning.

Secondary Outcome Measures

Name	Time	Method
Depressive Symptoms	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.	Assessed using the Beck Depression Inventory-II (BDI-II), a 21-item self-report questionnaire with total scores ranging from 0 to 63. Higher scores indicate greater severity of depressive symptoms
Subjective Sleep Quality	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.	Sleep quality will be assessed using the Pittsburgh Sleep Quality Index (PSQI), a self-questionnaire that evaluates sleep quality over the past month. It generates a global score ranging from 0 to 21, with higher scores indicating poorer sleep quality.
Analgesic Use	Analgesic use during the run-in period (Weeks 1 to 3) and throughout the treatment phase (Weeks 4 to 7).	The use of analgesics will be assessed by recording the number of tablets of each analgesic taken per week during the run-in period (Weeks 1 to 3) and throughout the treatment phase (Weeks 4 to 7)
Functional Capacity	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.	Functional interference of pain is assessed using the Brazilian Profile of Chronic Pain: Screen (B-PCP: S), which captures pain intensity, interference in daily life, and emotional impact. Scores range from 0 to 100, with higher scores indicating greater pain-related interference and effects.
Heat Pain Threshold	Assessment timepoints: Baseline; Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine)	Heat pain threshold will be assessed via quantitative sensory testing (QST) on the left forearm using a thermode that increases temperature from 30°C to 52°C at a rate of 1°C per second. The pain threshold is calculated as the average temperature at which pain is first reported across three trials. Higher values indicate greater pain threshold.
Circadian Profile (Chronotype)	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.	Chronotype will be measured using the Munich ChronoType Questionnaire (MCTQ) which evaluates individual sleep-wake patterns and chronotype based on the timing of sleep on workdays and free days. The key metric is the mid-sleep point on free days (MSF), which is based on sleep onset and wake-up times. The corrected version (MSFsc) accounts for workweek sleep debt and better reflects chronotype: lower values indicate morning types; higher values, evening types.
Objective Sleep and Activity (Actigraphy)	Actigraph use during the run-in period (Weeks 1 to 3) and throughout the treatment phase (weeks 4 to 7)	Actigraphy (accelerometer) assesses sleep quality and physical mobility. Mean values are calculated across days for parameters such as total sleep time, sleep efficiency, and activity levels. Higher sleep efficiency and activity indicate better sleep quality and physical functioning; lower values suggest disturbances or impairment.
Pressure Pain Threshold	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 will be measured using a pressure algometer applied to the left forearm. The threshold is defined as the point at which pressure sensation becomes painful, averaged across three trials. Higher values indicate lower pain sensitivity.
Cold Pressor Test Pain Intensity	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: Non-dominant hand immersed in ice water (\~1°C) for up to 2 minutes with continuous movement. Pain intensity is continuously rated via electronic visual analog scale (0-100%), enabling calculation of peak pain, mean pain, and area under the curve (AUC).allowing calculation of peak pain, mean pain, and area under the curve (AUC). Higher scores reflect greater pain intensity.
Patient-Defined Goals	Assessment timepoints: Baseline; Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine)	Patients will select three priority areas-physical, psychological, functional, or social-and define personalized, measurable goals at Visit 1 (V1) and evaluate them at the end of the treatment period (Visit 4).
Treatment Adherence	Assessment timepoints: Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine)	tDCS adherence: Assessed by the number and duration of valid sessions recorded by the device software, based on impedance and resistance parameters.; Pharmacological treatment adherence: Assessed by pill count at Visit 3 and Visit 4, based on the number of capsules consumed
Side Effects	Assessment timepoints: During the run-in period (Weeks 1 to 3) and throughout the treatment phase (Weeks 4 to 7).	The adverse effects of duloxetine will be assessed weekly throughout the run-in period (Weeks 1 to 3) and during the treatment phase (Weeks 4 to 7) using structured questionnaires that include common side effects such as nausea, dry mouth, dizziness, and somnolence, which will be recorded as 'yes' or 'no'. Adverse effects related to tDCS-such as tingling, itching, burning, or headache-will be assessed weekly during the treatment phase (Weeks 4 to 7), also using 'yes' or 'no' responses.
Satisfaction with Treatment	Assessment timepoints: Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine)	Assessed using the Numeric Satisfaction with Treatment Scale (NSTS), ranging from 0 (not at all satisfied) to 10 (extremely satisfied).
Global Cognitive Function (MoCA)	Assessment timepoints: Baseline; Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine)	Cognitive function will be assessed using the Montreal Cognitive Assessment (MoCA), a screening tool for global cognition. Scores range from 0 to 30, with higher scores indicating better cognitive performance. A score below 26 is suggestive of cognitive impairment
Attention and Working Memory (Digit Span - WAIS-III)	Assessment timepoints: Baseline; Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine)	Attention and working memory will be assessed using the Digit Span subtest of the WAIS-III. The total score is based on correct forward and backward digit recall, with higher scores indicating better performance.
Processing Speed (Symbol Search - WAIS-III)	Assessment timepoints: Baseline; Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine)	Processing speed will be assessed using the Symbol Search subtest of the WAIS-III. The outcome is a scaled score ranging from 1 to 19, with higher scores indicating faster processing.
Inhibitory Control (Stop Signal Task)	Assessment timepoints: Baseline; Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine)	Inhibitory control will be assessed using the Stop Signal Task. The primary outcome is Stop Signal Reaction Time (SSRT), measured in milliseconds. Lower reaction times indicate better inhibitory control.
Cognitive Flexibility (Trail Making Test A and B)	Assessment timepoints: Baseline; Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine)	Executive function and cognitive flexibility will be assessed using the Trail Making Test Parts A and B. The outcome is total time to completion in seconds. Longer completion times indicate worse performance.

Trial Locations

Locations (1)

Hospital de Clínicas de Porto Alegre; 🇧🇷 Porto Alegre, Rio Grande do Sul, Brazil