Home-based Transcranial Direct Current Stimulation (tDCS) Compared to Duloxetine in the Treatment of Fibromyalgia: a Randomized Non-inferiority Clinical Trial (FIBROSTIM)
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 610
- 试验地点
- 1
- 主要终点
- Evaluation of Pain Interference
研究概览
简要总结
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
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.
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
(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.
干预措施: Transcranial direct current stimulation (tDCS) plus placebo. (Device)
(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.
干预措施: Home-based transcranial direct current stimulation (Device)
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.
干预措施: Transcranial direct current stimulation (tDCS) plus placebo. (Device)
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.
干预措施: Home-based transcranial direct current stimulation (Device)
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.
干预措施: Duloxetine (60 mg) once daily (Drug)
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.
干预措施: Duloxetine 60 mg (Drug)
结局指标
主要结局
Evaluation of Pain Interference
时间窗: 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
时间窗: 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
时间窗: 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.
Cognitive symptoms
时间窗: 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
时间窗: 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.
Cortical Electrical Activity
时间窗: 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 will be assessed using resting-state electroencephalography (EEG). Recordings will be performed in a quiet room, with participants seated comfortably and instructed to remain relaxed and still. EEG data will be collected during eyes-closed and eyes-open conditions using a 64-channel EEG system. Signals will be recorded with a band-pass filter of 0.3-200 Hz and a sampling rate of 250 Hz. Spectral power measures will be analyzed to characterize cortical oscillatory activity associated with pain processing and central sensitization in fibromyalgia.
次要结局
- 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.)
- 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.)
- Analgesic Use(Analgesic use 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.)
- 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))
- 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.)
- 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))
- 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))
- 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))
- 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))
- Treatment Adherence(Assessment timepoints: Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine))
- Side Effects(Assessment timepoints: During the run-in period (Weeks 1 to 3) and throughout the treatment phase (Weeks 4 to 7).)
- Satisfaction with Treatment(Assessment timepoints: Week 8 (Visit 4/after completing the four-week treatment with active [a-tDCS], sham [s-tDCS], or duloxetine))
- 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))
- 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))
- 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))
- 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))
- 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))