Home-based Transcranial Direct Current Stimulation (tDCS) Compared to Duloxetine in the Treatment of Fibromyalgia: a Randomized Non-inferiority Clinical Trial (FIBROSTIM)
Phase: NA
Conditions: Fibromyalgia (FM), tDCS, Duloxetine, BDNF, EEG
Sponsor: Hospital de Clinicas de Porto Alegre

 
 
 
 
 
Home-Based Transcranial Direct Current 
Stimulation (tDCS) Compared to Duloxetine in the 
Treatment of Fibromyalgia: A Randomized Non-
Inferiority Clinical Trial 
(FIBROSTIM) 
 
 
 
 
 
May 3, 2025 
 
 
 
 

PROTOCOL 
Home-Based Transcranial Direct Current Stimulation (tDCS) Compared to Duloxetine in the 
Treatment of Fibromyalgia: A Randomized Non-Inferiority Clinical Trial (FIBROSTIM)  
Study Design  
A randomized, non-inferiority, double-dummy, factorial, controlled, parallel-group clinical trial will be 
conducted.  
Sampling  
Recruitment and Informed Consent Process  
Participants will be selected from the database of the Pain and Neuromodulation Laboratory, 
which contains records of 2,700 patients who participated in the 2023-0210 study — “Mapping factors 
associated with symptom worsening and quality of care in primary care for fibromyalgia: a Brazilian 
population-based study.” These patients were recruited through large-scale media outreach. Among 
the questions assessed in the Mapping project, one asked about interest in participating in future 
studies — “Are you interested in participating in future studies of the Pain and Neuromodulation 
Laboratory?” (Response options: yes or no). Only participants who answered "yes" will be contacted.  
A member of the research team will contact participants via WhatsApp to invite them to 
participate, following the message in Appendix 1. It will be communicated that, in order to join the 
study, participants must first read and accept the online Informed Consent Form and then complete 
an online form (Appendix 2).  
If additional recruitment is needed to meet the required sample size, the study will be 
advertised in accordance with the HCPA’s communication guidelines. Appendix 3 contains the text 
that will be used for recruitment advertising if necessary (Recruitment Cover Letter – standard 
template).  
Inclusion Criteria:  
Participants will be right-handed women aged 18 to 75, with reading and writing proficiency, 
diagnosed with fibromyalgia according to the American College of Rheumatology (ACR) criteria 
established between 2010 and 2016. They must report a pain score of four or higher on the Numeric 
Pain Scale (NPS) on most days over the past 30 days. To be included in the study, patients must 
maintain the doses of medications to which they are refractory, except for analgesics. Doses of other 
medications must remain unchanged during the study period.  
Exclusion Criteria:  
Women who live more than 200 km from Porto Alegre, are pregnant, have decompensated 
systemic diseases, chronic inflammatory rheumatologic diseases, untreated hypothyroidism, a current 
or ongoing history of cancer, history of alcohol or drug abuse in the past 6 months, or decompensated 

psychiatric conditions with suicidal risk and a defined plan (based on a validated Suicide Risk 
Assessment Scale score) will be excluded.  
Additional exclusion criteria include the use of duloxetine doses greater than 60 mg/day. 
Contraindications to TMS and tDCS include metal implants in the brain, implanted medical devices 
in the brain, cardiac pacemakers, cochlear implants, neurological pathologies, history of traumatic 
brain injury or neurosurgery.  
Interventions  
The study includes 28 sessions of transcranial direct current stimulation (tDCS), either active 
or sham, combined with 60 mg duloxetine or placebo. Participants will be randomized according to 
the flowchart in Figure 2. All participants will receive a video-based educational intervention on 
fibromyalgia (https://youtu.be/riH7VcgpbSk) and daily exercise instructions.  
Transcranial Direct Current Stimulation (tDCS)  
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.  
Sham protocol: the same montage as active tDCS will be used, with current applied for 30 
seconds at the beginning, at 10 minutes, and at the end of the session. 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). Instructions are provided in Appendices 5 and 6.  
Pharmacological Intervention  
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).  
Procurement and preparation will occur in batches of 80 participants (48 placebo, 32 duloxetine), 
until the full sample of 610 is reached (244 duloxetine, 366 placebo).  
Pain Neuroscience Education (PNE)  
PNE aims to reduce fear and avoidance behaviors and improve treatment adherence. Based 
on scientific evidence, it explains chronic pain as a disease rather than a symptom. A video 
(https://youtu.be/riH7VcgpbSk) will be shared via WhatsApp, covering fibromyalgia mechanisms, 
related symptoms, and the importance of a multimodal treatment approach (Watson et al., 2019; 
Caneiro et al., 2021).  
Home Exercise Program  
All participants will be instructed to perform 17 simple exercises daily after each tDCS session. 
A video tutorial (https://youtu.be/CwkBLSYMwDQ) and printed guide (Appendix 01) will be 
provided. The exercises are safe, low-intensity, and focus on mobility, flexibility, and function. During 
the 3-week run-in phase (duloxetine titration), participants will perform 5 repetitions. Once tDCS 
begins, this will increase to 10 repetitions, maintained throughout the protocol and recommended for 
12 months of follow-up.  
Randomization  
Randomization will follow a 2:1:2 ratio, generated using sealedenvelope.com. Codes will be 
sealed in opaque envelopes, labeled with sequential numbers. An engineer, not involved in clinical 
care, will open the envelope and set up the tDCS device (active or sham). The study pharmacist, also 
blinded, will prepare the duloxetine/placebo kits.  
Blinding  
Researchers will receive pre-programmed tDCS devices without knowledge of the stimulation 
type. The compounding pharmacy will prepare and label medication kits according to the 
randomization schedule. Capsules of duloxetine and placebo will be visually identical.  
The pharmacist and a non-blinded researcher (not involved in data collection) will manage 
allocation. Labels will include the CAEE number, RedCap participant ID, pharmacist and PI names, 
drug/placebo identification, and storage instructions.  
To assess the success of blinding, participants will complete a structured questionnaire at the 
end of treatment to indicate their perception of the treatment received (active or placebo) and their 
confidence in that assessment.  
 

Sample size estimation and statistical analysis plan  
Sample size  
According to Pigeot et al.'s (2013) recommendations, the sample size was estimated using a 
formula composed of three factors. For the first factor, we used a standard normal distribution instead 
of t-quantiles. Therefore, we used z-values corresponding to a one-tailed significance level of 0.025 (z 
= 1.96) and a statistical power of 80% (z = 1.282), which is valid for large sample sizes.  
The second factor refers to Θ, which is 1 + f, where f is the retention fraction. For this 
calculation, we used f = -0.5, consistent with our hypothesis that (tDCS – placebo) would be no worse 
than at least 50% of (duloxetine – placebo) in patients with fibromyalgia. This margin was calculated 
based on clinical knowledge, the minimum clinically significant difference (MCID) (Mease et al., 2011), 
and recent evidence regarding treatment effects for fibromyalgia. These included the BPI global score 
(average pain intensity and pain interference) as the primary outcome (Chiarotto et al., 2019), and 
other key outcomes such as the Patient Global Impression of Improvement (PGI-I) (Geisser et al., 
2010), fibromyalgia-related quality of life (FIQ), self-reported executive functioning (BDEFS), and 
pain modulation via descending inhibitory pathways (DPIS, by CPM test), all of which were designated 
as primary endpoints in the present study.  
We used a conservative approach to define the non-inferiority margin, considering the smallest 
differences in any of our five predefined outcomes. Based on a recent meta-analysis (36 studies, n = 
11,930) (Farag et al., 2022), the effect sizes on pain scores (intensity and interference) for FDA-
approved fibromyalgia treatments (pregabalin, duloxetine, or milnacipran) are SMD, -0.30 (95% CI, 
−0.32 to −0.27), −0.33 (95% CI, −0.36 to −0.30), and −0.17 (95% CI, −0.20 to −0.15), respectively. 
These effect sizes represent, on average, a change between 10% and 20% in pain scores. On the other 
hand, according to our recent meta-analysis on the effects of tDCS for fibromyalgia (16 studies, n = 
813) (Teixeira et al., 2023), the impact of M1 tDCS on pain scores (including the BPI global score) 
was SMD = -0.81 (95% CI, -1.19 to -0.43).  
For PGI, FIQ; BDEFS, DPIS the effect sizes were not reported in the published meta-
analysis, so we decided to use a conservative SMD of 0.5. These effect sizes denote, on average, a 
change between 14% and 25% in pain scores. Additionally, the MCID for fibromyalgia is a change of 
2 points in the pain score (intensity or interference) on a scale from 0 to 10, representing at least a 
20% change in pain scores. Given this evidence, we used a conservative margin of 50% of the 
medication effect, representing 10% of pain changes (half the MCID value). This conservative 
approach was used in our previous non-inferiority studies on tDCS (Brunoni et al., 2017).  
The third factor requires determining ε and r. ε indicates that the standard deviation is 
associated with the mean difference of values. Based on the previous meta-analysis, it ranges from 1.2 
to 3 (Farag et al., 2022; Teixeira et al., 2023). In this study, we considered 3 (the highest reported value) 
as a conservative approach, due to the greater variability in responses reported in fibromyalgia patients. 
Additionally, r is the ratio between the relative efficacy (i.e., minus the placebo) of tDCS and the active 
comparator. Considering the results of the recent meta-analysis, we calculated by dividing the lower 
bound of the pooled mean differences, M1 tDCS = -0.43/medication = -0.30; thus, r = 1.30. The 
calculation was then performed as follows:  

Narm ≥ (1.96 + 1.282)^2 * (1+0.5^2 + (1-0.5)^2) * [(3)/(1.30-0.5)]^2 Narm ≥ 10.51 * 1.50 * 14.06 
Narm ≥ 221.7  
Considering a dropout rate of 10% (like our previous home-based tDCS studies) (Brietzke et 
al., 2019), we determined that a total sample of 244 per arm would be required to reject the null 
hypothesis (non-inferiority based on BPI global score changes). The sample size calculation assumed 
a  
 
fixed-sample design; however, an interim analysis is planned using the O’Brien-Fleming approach, 
which preserves the overall one-sided type I error rate (α = 0.025).  
Finally, the allocation ratio will be 2:2:1, also based on Pigeot et al. (2003), which recommends 
1:1:kp—i.e., a similar ratio for active treatments—while kp is determined according to the retention 
fraction (control), which we set at 0.5. Thus, this means that 244, 244, and 122 patients are allocated 
to (active M1 tDCS + placebo medication), (sham tDCS + duloxetine 60 mg), and (sham tDCS + 
placebo medication), respectively. Therefore, the estimated total sample size will be 610 participants.  
The sample size was estimated based on the composite mean of pain interference domains, 
which reflects the multidimensional nature of the pain phenomenon and presents the highest 
variability among the clinical outcomes assessed. The estimation followed the model proposed by 
Pigeot et al. (2013), which considers three main components: (1) the expected effect size (delta), (2) 
the estimated variability (standard deviation of the multidimensional mean), and (3) the significance 
level adjusted by the Bonferroni correction, along with the desired statistical power. As the BPI global 
score presented the highest variability and lowest expected effect size among the five co-primary 
endpoints, the estimated sample ensures sufficient power (≥80%) for all endpoints after Bonferroni 
correction.  
The adoption of multiple primary endpoints (five) is justified by the clinical complexity of 
fibromyalgia, for which treatment response cannot be adequately evaluated by a single indicator. A 
Bonferroni correction will be applied to control the family-wise error rate (FWER), with a global one- 
sided significance level of α = 0.025, equally divided among the five primary endpoints. In accordance 
with good clinical trial practice guidelines, each test will only be considered statistically significant if p 
< 0.005, ensuring statistical rigor and preventing type I error inflation.  
 
Interim Analysis and Early Termination Criteria  
This study includes five primary endpoints, all based on non-inferiority hypotheses, selected 
for their clinical relevance and the need for a multidimensional assessment of treatment response. The 
endpoints were chosen to capture distinct core domains affected by chronic pain, particularly in 
fibromyalgia. These include functional interference, global impression of improvement, quality of life, 
executive functioning, and the integrity of descending pain modulation mechanisms. The adoption of 
multiple primary endpoints is justified by the complex and multifactorial nature of fibromyalgia, for 

which treatment response cannot be adequately, evaluated using a single clinical indicator. The aim is 
to provide a comprehensive and clinically meaningful assessment of the intervention’s effects.  
A Bonferroni correction will be applied to control the family-wise error rate (FWER). The 
global one-sided significance level will be maintained at α = 0.025, divided equally among the five 
primary endpoints. Accordingly, each non-inferiority test will only be considered statistically 
significant if the p- value is less than 0.005. This approach ensures statistical rigor and minimizes type 
I error inflation due to multiple confirmatory comparisons, in accordance with good clinical trial 
practice guidelines.  
An interim analysis will be conducted after approximately 75% of the planned sample size has 
been accrued. The purpose is to evaluate futility, safety, and preliminary efficacy. This analysis will be 
carried out by an Independent Data Monitoring Committee (DMC), using a spending function based 
on the O’Brien-Fleming approach to preserve the global one-sided type I error rate of 0.025.  
 
The DMC may recommend early termination of the trial based on the following criteria:  
Efficacy (non-inferiority confirmed with high confidence): One or more primary endpoints 
(functional interference, global impression of improvement, quality of life, executive functioning) 
reach a p- value below the O’Brien-Fleming adjusted threshold for interim analysis (approximately p 
< 0.001), indicating robust statistical evidence of non-inferiority.  
Futility (low probability of achieving the endpoint at final analysis): Based on interim data, the 
conditional power is less than 20% to demonstrate non-inferiority for all primary endpoints.  
Safety: The occurrence of unexpected serious adverse events related to the intervention at a frequency 
higher than expected, with relevant clinical impact.  
Critical discontinuation/adherence issues: a dropout rate greater than 40% in any group, potentially 
affecting the validity of the results, as judged by the DMC.  
All DMC decisions will be formally recorded in meeting minutes and promptly communicated to both 
the study team and the ethics committee, following the procedures defined in the monitoring plan.  
 
Statistical Analysis  
Continuous and categorical variables were compared using Fisher’s exact test, the chi-square 
test, and the t-test for independent samples. The Shapiro-Wilk normality test was applied to determine 
the normal distribution of continuous variables. A Linear Mixed-Effects Regression Models for 
Repeated Measure (LMM) assessed primary outcomes (pain severity and disability) with treatment, 
placebo response (responder vs. non-responder), time, and the treatment-by-time interaction as fixed  

effects, and included a random intercept for patients to account for time differences. If appropriate, 
we then performed the Bonferroni’s Test adjustment for post hoc multiple comparisons to identify 
differences between the groups at each time point and used a paired t test to assess the effects on each 
experimental group. The Generalized Linear Model (GLM) will be used to examine the treatment 
effect on the secondary outcomes including quality of life, HPT, PGI-I and the descending pain 
inhibitory system (DPIS). The treatment effect on primary and secondary outcomes might be adjusted 
for analgesic use. Analgesic use was included in the model to control a potential confounder affecting 
pain outcomes. This ensures that the observed effects of a-tDCS, duloxetine and s-tDCS are 
attributable to the interventions rather than variations in analgesic use, thereby enhancing the validity 
of the results. All analyses were adjusted for multiple comparisons using Bonferroni’s Test. The 
modified ITT (m- ITT) analysis included those completing ≥50% of sessions, with missing data 
imputed using regression model coefficients. In the m-ITT, with an adjusted protocol, encompassing 
all patients who completed at least ten sessions. The choice of ten sessions for ITT was guided by 
most of the literature supporting clinical symptom improvement in chronic pain (McCoy. 2017, 
Caumo, 2024). This method is not as strict as classical ITT, but it suggests that A-tDCS could be 
useful in clinical settings with at least a minimum number of sessions. Specifically, we replaced missing 
values with imputed data derived from a regression model using observed data. The treatment group 
served as the predictor, and the outcome variable with missing values was imputed based on regression 
coefficients, indicating the relationship between the treatment group and the outcome. This 
imputation method was applied, for example, to ten patients who withdrew after ten tDCS sessions. 
Sensitivity analyses confirmed consistent LMM results with or without imputation.  
The standardized difference means (SDM) was used to compute the effect size (ES) by 
dividing the mean difference between a-tDCS and s-tDCS by the pooled baseline standard deviation 
(SD). The ES was interpreted as small if lower than 0.20 to 0.49, moderate if between 0.50 and 0.79, 
and large if larger than 0.80 (Kazis ̧1954). All statistical analyses were performed using two-tailed tests 
at the 5% significance level with SPSS, version 22.0 (SPSS, Chicago, IL). 
  
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