Non-Invasive Brain Stimulation and Cognitive Training for Depressive Symptomatology Related to Breast Cancer (ONCODEP)

Study Overview
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Brief Summary
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The goal of this clinical trial is to test a home-delivered intervention that combines Non-Invasive Brain Stimulation techniques (transcranial direct and alternating current stimulation -tDCS and tACS-) and Online Cognitive Training (OCT) to treat depressive symptomatology and cognitive decline associated with breast cancer. The main questions aims to be answered are: To analyze the efficacy and feasibility of the intervention to treat depressive symptomatology. To analyze the efficacy and feasibility of the intervention to treat cognitive decline. To evaluate the medium and long-term effects (1, 3 and 6 months) of intervention. An OCT program and a portable wireless tDCS/tACS system will be used to perform the intervention at home. Patients will be divided into four treatment groups, depending on whether they will receive the OCT applied independently or combined with tDCS/tACS active or sham. In addition, saliva samples will be collected to identify bomarkers predictive of treatment efficacy.

Detailed Description
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This study is aimed at analyzing the feasibility and therapeutic efficacy of a home-based treatment using tDCS/tACS and an OCT program to treat depressive symptomatology (primary outcome variable) associated with breast cancer.The effect of the intervention on the patients' cognitive functioning (secondary outcome variable) will be also studied. In addition, saliva biomarkers and other clinical variables will be analyzed to determine whether they are related to the response to treatment. Finally, the impact of the intervention on the burden of the relatives/caregivers will be studied. Oncology Units of the Galician Health Service will be contacted for recruitment. Oncologists will review whether patients meet the inclusion criteria and none of the exclusion criteria. If so, patients will be given an information flyer and will contact the research team to receive more information and, if they wish, to participate in the study. If patients are interested in participating, researchers will contact them to confirm the inclusion/exclusion criteria and participants will be invited to the first face-to-face session. In this session, informed consent will be signed, pre-treatment neuropsychological assessment will be performed, medical data will be reviewed, and a saliva sample will be collected. After collecting this data, the first treatment session will take place in the presence of the researcher. The type of treatment each patient will receive (OCT, tDCS active+ OCT, tACS active+ OCT or sham neurostimulation+ OCT. ) will be chosen randomly, using a randomization list. After that, each patient will undergo 14 sessions, daily, at home. The tES devices (Soterix Medical Inc) have been designed for home use and allow the application of the stimulation by the patient himself, while being monitored by the researcher. The OCT will be delivered through NeuronUp2GO platform.Possible adverse effects associated with neurostimulation (which are mild and transitory) and other variables that may affect its efficacy (medication diary, caffeine intake...) will be monitored daily. Finally, a post-treatment assessment will be carried out 15 days after the start of treatment and a follow-up assessment will be carried out 1, 3 and 6 months after the end of treatment. The 15-day and 1 month assessments will be the same as the pre-treatment (questionnaries and neuropsychological test). The follow-ups at 3 and 6 months will be done online, by filling in questionnaires. Both the treatment administration and analysis of the results will be blinded. First, descriptive analyses will be performed on the sociodemographic and clinical data. To evaluate the efficacy of the treatments on depressive symptomatology and subjective cognitive complaints, ANOVAs will be calculated under classical and Bayesian statistical frameworks, with Group (4 arms) as inter-participant factor and Time (pre, post, 1, 3 and 6 months follow-up) as intra-participant factor, following an Intention-to-Treat approach (including possible missing data after randomization). ANOVAs will also be calculalted with with Group (4 arms) as inter-participant factor and Time (pre, post, 1 month follow-up) as intra-participant factor to calculate the efficacy of the treatments on neuropsychological indexes. The possible modulating effect of sociodemograpchic and clinical variables on treatment efficacy will be analyzed. Also, for the clinical validation of the treatments, the analysis of the Minimal Clinically Important Difference (MCID) at short (15 days), medium (1 month) and long term (3 and 6 months) will be included. The difference between the pre- and post-treatment assessment in the primary and secondary variable scores should be equal to or greater than 30%. Proteomic analysis will be performed at the Fundación Biomédica Galicia Sur. The following analysis will be performed: determination of total protein, mass spectrometry and electrophoretic separation of the samples by SDS-PAGE and identification of the bands of interest by Shotgun. The whole sample will be analyzed in liquid mass spectrometer (LC-MS/MS). Linear or logistic regression analysis will be performed to determine the predictive power of the saliva biomarkerson treatment efficacy. Since the present research involves adult humans, it will be conducted under applicable international, EU and national laws and regulations (The Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects; The International Conference on Harmonisation (ICH)/Good Clinical Practice (GCP) Guidelines; the Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine; and the UNESCO Universal Declaration on Bioethics and Human Rights (2005). Permission has been obtained from the local IRB committee (CEIm de Galicia) to conduct the study. In terms of data protection, this study complies with the directives of the General Data Protection Regulation (GDPR), approved by the European Commission on April 27, 2016 (EU 2016/679) and with the Organic Law 3/2018, of December 5, 2018, on the Protection of Personal Data and guarantees of digital rights. The storage and treatment of the samples will be carried out in accordance with the Biomedical Research Law 14/2007 and RD 1716/201. Patients' clinical data will be collected in the study-specific data collection notebook using REDCap (Research Electronic Data Capture), a secure web-based application for building and managing online surveys and databases. Data collection will be pseudo-anonymous, protecting the identity of the participant. Only the principal investigator of the entity responsible for data collection (USC) will know the pseudonymization codes. The research team will have access to all coded data collected for the study.

Official Title
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Intervention With Non-Invasive Brain Stimulation and Cognitive Training for Depressive Symptomatology Associated With Breast Cancer (ONCODEP)

Conditions
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Depressive Symptoms, Cognitive Impairment

Intervention / Treatment
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* Device: Transcranial Direct Current Stimulation
* Device: Transcranial Alternating Current Stimulation
* Device: tES sham
* Device: Online Cognitive Training


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of breast cancer in early stages (life expectancy greater than 12 months). Patients who are receiving or have finished (maximum 6 months prior to participation in the participating in the study) some type of oncological treatment (Chemotherapy, Radiotherapy, Immunotherapy, Hormonal Therapy). Patients whose mother tongue is Galician or Spanish. Ability to give informed consent. Present depressive symptomatology: score of 4 or higher in the BDI-FS. Ability to use WhastApp Have access to some technology (desktop computer, laptop or tablet) and the Internet (Firefox or Chrome browsers). Exclusion Criteria: Pregnant or breastfeeding women. Patients with metastasis. Patients with a history of psychiatric symptomatology (depressive disorder, bipolar,anxious, psychotic...) prior to the oncological process. Patients with a history of cognitive impairment or dementia prior to the oncologic process. oncological process. Patients with a history of neurosurgery, cortical lesions or neurological alterations prior to the oncological process. Patients with history or current consumption of non-prescribed drugs. Patients with the following medication regimen: mood stabilizers, antipsychotics, anticonvulsants, l-dopa, rivastigmine, dextromethorphan, flunarizine, sulpiride, use of benzodiazepines (excluding long half-life benzodiazepines (Bromazepam, Diazepam) on a continuous/habitual basis,Alprazolam >1mg per day, Lorazepam >2mg per day). Patients taking antidepressant medication should have a stable regimen ( same medication at the same dose for a minimum of four weeks prior to entering the study.The regimen with antidepressant drugs or drugs used as treatment to improve cognition should be kept stable during the entire participation (until the follow-up evaluation has been performed). Patients unable to complete a neuropsychological examination. Patients who are participating in a research study/clinical trial with drugs. Patients who present any condition contraindicated to undergo tES (intracranial ferromagnetic devices or implanted stimulators; history of active epilepsy; history of neurosurgery, traumatic brain injury with loss of brainwith loss of consciousness and/or cortical lesion) (Antal et al., 2017)

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, four-arm, placebo-controlled, parallel-structured, double-blinded clinical trial.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Online Cognitive Training<br>15 sessions of 20 minutes each one.Training will focus on the stimulation of several cognitive functions (attention, memory and learning, language, executive functions,processing speed, etc) through different exercises. The sessions will be adjusted to the individual performance level. The participant will perform these exercises from their computer or tablet, through the NeuronUp2GO platform, and the researcher will have access to all the session data. | Device: Online Cognitive Training<br>* OCT<br>* Other names: OCT;|
| Experimental: Transcranial Direct Current Stimulation<br>tDCS: 15 daily sessions targeting left DLPFC (anode: F3, cathode: Fp2) Current intensity will be set at 2mA and will be applied for 20 minutes, with 15-second ramps up and down at the beginning and end of the stimulation period. During the session, the participant will be performing the OCT. | Device: Transcranial Direct Current Stimulation<br>* tDCS+OCT<br>* Other names: tDCS;Device: Online Cognitive Training<br>* OCT<br>* Other names: OCT;|
| Experimental: Transcranial Alternating Current Stimulation<br>tACS: 15 daily sessions targeting left DLPFC (anodes: F3, F4; frequency: 4Hz -theta-tACS-). Current intensity will be set at 2mA and will be applied for 20 minutes, with 15-second ramps up and down at the beginning and end of the stimulation period. Participant will be performing the OCT during stimulation. | Device: Transcranial Alternating Current Stimulation<br>* tACS+OCT<br>* Other names: tACS;Device: Online Cognitive Training<br>* OCT<br>* Other names: OCT;|
| Sham Comparator: tES sham<br>15 sessions of sham stimulation for 20 minutes, acting as a placebo control group. The electrode montage will be the same as that used in the active neuromodulation conditions: tDCS for half of the participants and tACS for the other half. In this sham stimulation condition, the current will only be delivered for a 15 seconds, at the ramp-up and ramp-down times at the beginning and end of the session. The OCT will also be the same as those performed by participants in the other groups | Device: tES sham<br>* tES sham + OCT<br>Device: Online Cognitive Training<br>* OCT<br>* Other names: OCT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Beck Depression Inventory- Fast Screen (BDI-FS) | Screening of depressive symptoms in medical patients (7 items, scored on a Likert scale from 0 to 3). BDI-FS minimum and maximum values range from 0 to 21, with higher scores meaning more depressive symptomatology. | pre-, post- intervention (15 days) and follow-up (1,3,6 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient Reported Outcomes Measurement Information System (PROMIS) Cognitive Function 8a | To assess subjective cognitive complaints in the last week (8 items, scored on a Likert scale from 1 to 5). Minimum and maximum values rang from 8 to 40. Lower scores mean more subjective cognitive complaints. | pre-, post- intervention (15 days) and follow-up (1,3,6 months) | 
| Montreal Cognitive Assessment (MoCA) | Cognitive impairment screening that explores attention, concentration, executive functions, memory, language, visual-constructive abilities, calculation and orientation (10 minutes). Minimum and maximum values range from 0 to 30. Lower scores mean better cognitive functioning, The cutoff point for Mild Cognitive Impairment is 26. | pre-, post- intervention (15 days) and follow-up (1month). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Depressive Symptoms, Non-Invasive Brain Stimulation, Cognitive Training, Cognitve Impairment, Breast Cancer