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

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

NA

Total Enrollment

610 participants

Study Classification

INTERVENTIONAL

Study Start Date

2025-09-30

Study Completion Date

2028-12-31

Brief Summary

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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

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Detailed Description

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Conditions

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Fibromyalgia (FM) tDCS Duloxetine BDNF EEG

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

FACTORIAL

Arm 1: Duloxetine + Sham tDCS (n = 244) Duloxetine 60 mg/day plus 28 sessions of sham tDCS (30s stimulation at start, 10 min, and end), with electrodes placed over left M1 (anode) and right supraorbital area (cathode), using 35 cm² electrodes. Sessions are home-based, 20 minutes/day for 4 weeks.

Arm 2: Active tDCS + Placebo (n = 244) Active tDCS (2 mA, 20 minutes/day for 4 weeks) using the same montage, plus oral placebo. Sessions are home-based following in-person training. The device monitors contact impedance and logs session data.

Arm 3: Sham tDCS + Placebo (n = 122) Sham tDCS and oral placebo, using the same procedures as above.

Common to all arms:

All participants receive home-based physical exercise guidance and pain neuroscience education. Duloxetine and matching placebo (30 mg and 60 mg) are prepared and labeled by a compounding pharmacy using a double-dummy design. Medication kits follow a titration and tapering schedule and are dispensed at study visits.

Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Researchers will receive a tDCS device pre-programmed by biomedical engineering, without prior knowledge of whether the condition is active or sham.

The compounding pharmacy contracted for the study will prepare the placebo and fractionate the Duloxetine Hydrochloride. Researchers will receive a kit containing four labeled containers:

Containers 1 and 4 (white lid): 7 capsules of either placebo or Duloxetine 30 mg

Container 2 (green lid): 16 capsules of either placebo or Duloxetine 60 mg

Container 3 (green lid): 42 capsules of either placebo or Duloxetine 60 mg

Each container will display the randomization ID and will be properly labeled. Allocation information will be accessible only to the responsible pharmacist (who is not involved in data collection) and the researcher who performed the randomization (with no contact with participants). Labels will include the project number (CAAE), participant ID (RedCap), and pharmacist's name.

Study Groups

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

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.

Group Type SHAM_COMPARATOR

Transcranial direct current stimulation (tDCS) plus placebo.

Intervention Type DEVICE

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 adherence, interrupting the session if impedance exceeds 1 mA (5-second interval) or if current varies \>10%. Developed in partnership with HCPA's Biomedical Engineering, the device is licensed by UFRGS/HCPA and registered with ANVISA (No. 80079190028).

Home-based transcranial direct current stimulation

Intervention Type DEVICE

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

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

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.

Group Type EXPERIMENTAL

Transcranial direct current stimulation (tDCS) plus placebo.

Intervention Type DEVICE

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 adherence, interrupting the session if impedance exceeds 1 mA (5-second interval) or if current varies \>10%. Developed in partnership with HCPA's Biomedical Engineering, the device is licensed by UFRGS/HCPA and registered with ANVISA (No. 80079190028).

Home-based transcranial direct current stimulation

Intervention Type DEVICE

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

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.

Group Type ACTIVE_COMPARATOR

Duloxetine (60 mg) once daily

Intervention Type DRUG

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 number, participant ID (RedCap), pharmacist and PI names, and storage/use instructions. Kits will be stored at the HCPA Pharmacy Service under controlled conditions and dispensed during visits AV1 (Jars 1 and 2), AV2 (Jar 3), and AV3 (Jar 4).

Duloxetine 60 mg

Intervention Type DRUG

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 number, participant ID (RedCap), pharmacist and PI names, and storage/use instructions. Kits will be stored at the HCPA Pharmacy Service under controlled conditions and dispensed during visits AV1 (Jars 1 and 2), AV2 (Jar 3), and AV3 (Jar 4).

Interventions

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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 adherence, interrupting the session if impedance exceeds 1 mA (5-second interval) or if current varies \>10%. Developed in partnership with HCPA's Biomedical Engineering, the device is licensed by UFRGS/HCPA and registered with ANVISA (No. 80079190028).

Intervention Type DEVICE

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 number, participant ID (RedCap), pharmacist and PI names, and storage/use instructions. Kits will be stored at the HCPA Pharmacy Service under controlled conditions and dispensed during visits AV1 (Jars 1 and 2), AV2 (Jar 3), and AV3 (Jar 4).

Intervention Type DRUG

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

Intervention Type DEVICE

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 number, participant ID (RedCap), pharmacist and PI names, and storage/use instructions. Kits will be stored at the HCPA Pharmacy Service under controlled conditions and dispensed during visits AV1 (Jars 1 and 2), AV2 (Jar 3), and AV3 (Jar 4).

Intervention Type DRUG

Eligibility Criteria

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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

Minimum Eligible Age

18 Years

Maximum Eligible Age

75 Years

Eligible Sex

FEMALE

Accepts Healthy Volunteers

No