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Safety and Efficacy of tDCS in Pediatric DoC (tDCS-DoC-Ped)

Primary Purpose

Disorder of Consciousness

Status
Not yet recruiting
Phase
Not Applicable
Locations
Study Type
Interventional
Intervention
tDCS
sham tDCS
Sponsored by
Giovanna Cristella
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Disorder of Consciousness focused on measuring Pediatric population, tDCS, disorder of consciousness

Eligibility Criteria

4 Years - 17 Years (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Ages between 4 and 17; prolonged condition (>3 and <12 months) of MCS and VS by severe brain injury; admission to the paediatric rehabilitation department of the Don Carlo Gnocchi Foundation in Florence; central nervous system drug therapy stable for at least one week; stable DoC (i.e. no change in DoC diagnosis detected by 2 consecutive CRS-Rs performed one week apart); Signature of informed consent by the legal representative. Exclusion Criteria: Presence of extensive focal lesions in the left dorsolateral prefrontal cortex (DLPFC); radiological evidence of blood collection/liquid collection/other between the DLPFC and the anode placement site; seizures in the previous month; seizures and/or intermittent epileptiform discharges observed at the extended EEG during the screening phase or at any of the EEG recordings during participation in the study; Presence of established pregnancy; History of cranial surgery, presence of metallic, cochlear or electronic brain implant in the head or neck area, or ventricular shunt to pacemaker; Need for mechanical daytime ventilation; Head circumference less than 43 cm; bilateral severe or profound hypoacusia; Presence of skin lesions in the area to be stimulated; Taking sedative drugs and/or Na or Ca channel blockers or NMDA receptor antagonists presence of peritoneal ventricle shunt in the stimulated area (prefrontal cortex); serious clinical conditions that may influence the clinical diagnosis (e.g. severe liver failure or kidney).

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Sham Comparator

    Arm Label

    Active Comparator - real tDCS

    Sham Comparator - sham tDCS

    Arm Description

    real tDCS: anodal transcranial direct current stimulation were delivered over the left DLPF cortex in patients

    sham transcranial direct current stimulation were delivered over the left DLPF cortex in patients.

    Outcomes

    Primary Outcome Measures

    Evaluating the safety of tDCS treatment assessing the change over time
    the ratio of reported adverse events between the two treatment groups and the proportion of treatments discontinued for adverse events will be assessed, using an "Adverse Event Collection Form" completed by a practitioner other than the parents will be used
    Assessing the change of tolerability of treatment with tDCS
    Face, Legs, Activity, Cry and Consolability Scale (FLACC 0-10 worst value) scale will be used to assess tolerability of treatment
    Assessing the change in the state of consciousness by using tDCS
    Coma Recovery Scale - Revised (CRS-R 0-23 best value) will be used to evaluate the effectiveness of tDCS

    Secondary Outcome Measures

    To evaluate the effect of tDCS stimulation on brain electrical activity
    analysis of EEG signal coherence measurements before and after the stimulation cycle
    To evaluate the effect of tDCS stimulation on cortical electrical activity
    cortical components analysis of event-related potentials (ERPs) before and after the stimulation cycle;
    To evaluate the effect of tDCS stimulation in determining haemodynamic response (HDR) changes quantifiable
    Functional Near Infrared Spectroscopy (fNlRS): spectroscopic analysis at the level of stimulated areas after treatment
    Assess caregiver satisfaction with the treatment
    Family Feedback Form Questionnaire will be submitted to caregivers

    Full Information

    First Posted
    May 9, 2023
    Last Updated
    September 5, 2023
    Sponsor
    Giovanna Cristella
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    1. Study Identification

    Unique Protocol Identification Number
    NCT05929274
    Brief Title
    Safety and Efficacy of tDCS in Pediatric DoC
    Acronym
    tDCS-DoC-Ped
    Official Title
    Safety and Efficacy of Transcranial Direct Current Stimulation in Pediatric Disorders of Consciousness
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    September 2023
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    October 2023 (Anticipated)
    Primary Completion Date
    July 2028 (Anticipated)
    Study Completion Date
    July 2028 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor-Investigator
    Name of the Sponsor
    Giovanna Cristella

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Product Manufactured in and Exported from the U.S.
    No
    Data Monitoring Committee
    No

    5. Study Description

    Brief Summary
    Background: Despite established evidence supporting the use of tDCS in the adult patient with disorders of consciousness, its use in paediatric patients with brain injury is still limited. Regarding the use of tDCS in paediatric patients with DoC, the scientific evidence still appears to be preliminary about the safety profile and requires further data before investigating efficacy on a broad scale. In fact, although the method has been shown to be safe in other clinical conditions, efficacy and tolerability in children with DoC may vary significantly depending on differences in activation threshold and the presence of underlying pathological electrical activity The implementation of clinical trials investigating the safety and tolerability of tDCS in paediatric patients with DoC now represents an essential first step for a future determination of the efficacy of this method in a population for which therapeutic options are currently extremely limited Objective: The study aim to verify the safety of tDCS treatment and to evaluate the effectiveness of stimulation of the left dorsolateral prefrontal cortex by tDCS in promoting improvement in the level of consciousness in paediatric patients with Disorders of Consciousness. Method: in this mono-center, randomised, double blind cross-over controlled pilot study, real or sham tDCS were applied to the left dorsolateral prefrontal (DLPF) cortex of paediatric patients with disorders of consciousness for two weeks, followed by two weeks of washout, then real or sham tDCS were applied to the left dorsolateral prefrontal (DLPF) cortex for other two weeks, followed by another two weeks of washout.
    Detailed Description
    Introduction Following a severe acquired brain injury of traumatic, hypoxic-anoxic, or vascular origin, conditions of very severe cognitive and motor impairment can occur, named as Disorders of Consciousness (DoC), which include the Vegetative State (VS), characterized by the presence of vegetative functions 'in absence of self-awareness and awareness of the environment, and the Minimal Consciousness State (MCS), in which minimal, inconstant, but repeated behavioral responses to visual, verbal or nociceptive stimuli are recognizable, clearly distinguishable from reflex responses. Differential diagnosis can be complex, and one of the first (and most frequent) sign of transition from VS to MCS is the appearance of visual tracking of salient stimuli .The natural evolution of DoC is influenced by the etiology, being anoxic forms less favorable to recover than other forms. It has been proven that patients with MCS have more favorable prognoses than patients with VS, especially when the condition of MCS occurs within a few months from the acute event. Despite significant improvement in the understanding of the neural correlates of DoC, the treatment options currently available for these patients are still very limited. Recent findings, however, suggest a broad spectrum of therapeutic possibilities. In the last decade, in fact, several studies have reported signs of spontaneous improvement of consciousness a few years after the acute event in some patients diagnosed with VS .Furthermore, studies on treatments that enhance cognitive abilities in patients with DoC have shown that deep brain stimulation (DBS) in the intralaminar nuclei of the thalamus and some drugs such as amantadine , intrathecal baclofen and zolpidem can improve sign of consciousness behavior in a large cohort of acute and sub-acute patients with DoC of traumatic origin in sham-controlled studies. In pediatric population with DoC, the exact incidence of VS and MCS is not entirely clear; however, it appears that MCS is more frequent condition than VS compared to adult patients After the acute phase, the pediatric DoC patient starts a specific rehabilitation pathway; its primary goal is the maximum possible recovery of consciousness. During intensive rehabilitation, about 2/3 of pediatric and young adult patients emerges to a state of consciousness within 7 months after the acute event. The rehabilitation program includes a neuropsychological approach dedicated to the recovery of consciousness; from a pharmacological point of view, the literature suggests the use of the following drugs for pediatric DoC: carbidopa-levodopa, amantadine, zolpidem, and methylphenidate. Efficacy During the last 20 years, intervention studies with innovative non-invasive brain stimulation techniques, such as transcranial direct current stimulation (tDCS), have shown that cycles of low-intensity electrical stimulation delivered via electrodes applied to the scalp in specific areas can promote the processes of neuronal plasticity, i.e. the ability of the central nervous system to modify its structure and functioning in response to new information and experiences. These effects appear to be particularly interesting in the treatment of various neurological and psychiatric disorders such as Parkinson's Disease, post-stroke aphasia or the neuropsychological outcomes of Multiple Sclerosis. More recently, tDCS has been shown to be a safe, inexpensive, and simple technique that can be easily integrated into rehabilitation programs. In particular, stimulation with tDCS has been shown to be effective in aiding the recovery of the state of consciousness in the adult population in the acute, subacute and chronic phase, predominantly in the MCS condition, considering traumatic and non-traumatic etiology. This occurs especially in the anodic stimulation mode of the left dorsolateral prefrontal cortex. In a study in which tDCS was applied for five consecutive days on the motor cortex and left prefrontal cortex in 10 chronic DoC patients, the effect of stimulation was evaluated up to 12 months after its ending, showing that even chronic DoC patients show signs of improvement and that this effect can be maintained up to 12 months after tDCS treatment. From a neurophysiological point of view, tDCS acts by increasing neuronal excitability and facilitating the action potential by modifying the excitability of N-methyl-D-aspartate (NMDA) receptors. In addition, tDCS can enhance active synaptic connections. The effect of a single tDCS session lasts approximately 60 to 90 minutes; when stimulation is repeated 10 times up to 20 sessions it has been found that the effects last up to 3 months after the ending of the stimulation sessions. Security The safety and tolerability of tDCS have been widely demonstrated in adult patients with consciousness disorders and brain damage. Most authors have found a very good safety profile in patients with DoC, recording adverse effects that are generally transient and mild. Common adverse effects reported during or immediately after tDCS include tingling or numbness in stimulated skin, headache, nausea and fatigue. In addition, there is currently no evidence of long-term adverse or serious adverse effects associated with the use of tDCS in adult DoC patients. The possibility of subclinical neuronal damage induced by stimulation has been ruled out in studies that assessed serum levels of neuron-specific enolase (NSE, a marker of neuronal damage) before and after stimulation and by studies with EEG or magnetic resonance imaging. Regarding the protocols utilized, this method has to be regarded as safe. Despite established evidence supporting the use of tDCS in the adult patient, its use in paediatric patients with brain injury is still limited. To date, tDCS is mainly used in paediatric age as a complementary therapy in the rehabilitation of neurodevelopmental disorders such as infantile cerebral palsy, attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder. In these patients, tDCS was confirmed to be a safe and well-tolerated technique even in the paediatric population with a small number of reported mild and short-lasting adverse events such as tingling (18%), discomfort (8%) and itching (7%). Regarding the use of tDCS in paediatric patients with DoC, the scientific evidence still appears to be preliminary about the safety profile and requires further data before investigating efficacy on a broad scale. In fact, although the method has been shown to be safe in other clinical conditions, efficacy and tolerability in children with DoC may vary significantly depending on differences in activation threshold and the presence of underlying pathological electrical activity. The implementation of clinical trials investigating the safety and tolerability of tDCS in paediatric patients with DoC now represents an essential first step for a future determination of the efficacy of this method in a population for which therapeutic options are currently extremely limited. Lastly, several studies have shown that certain quantitative measures of functional connectivity derived from electroencephalographic and evoked-potential analysis (e.g., coherence of the EEG signal, presence of event-related evoked potentials) are capable of faithfully reflecting changes in the state of consciousness in adult DoC patients, contributing to the formulation of prognosis and the identification of patients who are most likely to benefit from treatment. In this sense, the identification of possible paediatric neurophysiological biomarker can help to provide a preliminary quantitative measure of response to treatment, while contributing to the understanding of the effect of tDCS on involved brain networks.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Disorder of Consciousness
    Keywords
    Pediatric population, tDCS, disorder of consciousness

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Not Applicable
    Interventional Study Model
    Parallel Assignment
    Model Description
    Using a sham-controlled randomized double-blind design, 10 patients were randomly assigned to group A or B.
    Masking
    ParticipantOutcomes Assessor
    Allocation
    Randomized
    Enrollment
    10 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Active Comparator - real tDCS
    Arm Type
    Experimental
    Arm Description
    real tDCS: anodal transcranial direct current stimulation were delivered over the left DLPF cortex in patients
    Arm Title
    Sham Comparator - sham tDCS
    Arm Type
    Sham Comparator
    Arm Description
    sham transcranial direct current stimulation were delivered over the left DLPF cortex in patients.
    Intervention Type
    Device
    Intervention Name(s)
    tDCS
    Intervention Description
    Direct current was applied by a battery-driven constant current stimulator using saline-soaked surface sponge electrodes (7 3 5 cm) with the anode positioned over the left dorsolateral prefrontal cortex (F3 according to the 10-20 international system for EEG placement) and the cathode placed over the right supraorbital region. During real tDCS, the current was increased to 2 milliampere (mA) from the onset of stimulation and applied for 20 minutes.
    Intervention Type
    Device
    Intervention Name(s)
    sham tDCS
    Intervention Description
    For the sham condition (sham tDCS), the same electrode placement was used as in the stimulation condition, but the current was applied for only 5 seconds, and was then ramped down.
    Primary Outcome Measure Information:
    Title
    Evaluating the safety of tDCS treatment assessing the change over time
    Description
    the ratio of reported adverse events between the two treatment groups and the proportion of treatments discontinued for adverse events will be assessed, using an "Adverse Event Collection Form" completed by a practitioner other than the parents will be used
    Time Frame
    baseline (1-7 days), post-stimulation (within 30-minutes), follow-up (24 hours, 48 hours, 5 days)
    Title
    Assessing the change of tolerability of treatment with tDCS
    Description
    Face, Legs, Activity, Cry and Consolability Scale (FLACC 0-10 worst value) scale will be used to assess tolerability of treatment
    Time Frame
    Baseline (1-7 days), pre-during-post stimulation (pre-stimulation: within 30 minutes, during: within 20 minutes, post-stimulation: within 30-minutes)
    Title
    Assessing the change in the state of consciousness by using tDCS
    Description
    Coma Recovery Scale - Revised (CRS-R 0-23 best value) will be used to evaluate the effectiveness of tDCS
    Time Frame
    days 1, 8, 12, 19, 35, 40, 47, 62, 92
    Secondary Outcome Measure Information:
    Title
    To evaluate the effect of tDCS stimulation on brain electrical activity
    Description
    analysis of EEG signal coherence measurements before and after the stimulation cycle
    Time Frame
    days 1, 8, 35, 47, 62, 92
    Title
    To evaluate the effect of tDCS stimulation on cortical electrical activity
    Description
    cortical components analysis of event-related potentials (ERPs) before and after the stimulation cycle;
    Time Frame
    days 1, 8, 35, 47, 62, 92
    Title
    To evaluate the effect of tDCS stimulation in determining haemodynamic response (HDR) changes quantifiable
    Description
    Functional Near Infrared Spectroscopy (fNlRS): spectroscopic analysis at the level of stimulated areas after treatment
    Time Frame
    days 8, 35, 47, 62, 92
    Title
    Assess caregiver satisfaction with the treatment
    Description
    Family Feedback Form Questionnaire will be submitted to caregivers
    Time Frame
    days 19 and 47

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    4 Years
    Maximum Age & Unit of Time
    17 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Ages between 4 and 17; prolonged condition (>3 and <12 months) of MCS and VS by severe brain injury; admission to the paediatric rehabilitation department of the Don Carlo Gnocchi Foundation in Florence; central nervous system drug therapy stable for at least one week; stable DoC (i.e. no change in DoC diagnosis detected by 2 consecutive CRS-Rs performed one week apart); Signature of informed consent by the legal representative. Exclusion Criteria: Presence of extensive focal lesions in the left dorsolateral prefrontal cortex (DLPFC); radiological evidence of blood collection/liquid collection/other between the DLPFC and the anode placement site; seizures in the previous month; seizures and/or intermittent epileptiform discharges observed at the extended EEG during the screening phase or at any of the EEG recordings during participation in the study; Presence of established pregnancy; History of cranial surgery, presence of metallic, cochlear or electronic brain implant in the head or neck area, or ventricular shunt to pacemaker; Need for mechanical daytime ventilation; Head circumference less than 43 cm; bilateral severe or profound hypoacusia; Presence of skin lesions in the area to be stimulated; Taking sedative drugs and/or Na or Ca channel blockers or NMDA receptor antagonists presence of peritoneal ventricle shunt in the stimulated area (prefrontal cortex); serious clinical conditions that may influence the clinical diagnosis (e.g. severe liver failure or kidney).
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Giovanna Cristella, MD
    Phone
    0557393949
    Email
    gcristella@dongnocchi.it
    First Name & Middle Initial & Last Name or Official Title & Degree
    Martina Lombardini, MD
    Phone
    3281447917
    Email
    mlombardini@dongnocchi.it
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Giovanna Cristella, MD
    Organizational Affiliation
    IRCCS Fondazione Don Carlo Gnocchi ONLUS
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Plan to Share IPD
    No
    Citations:
    PubMed Identifier
    25448248
    Citation
    Chung MG, Lo WD. Noninvasive brain stimulation: the potential for use in the rehabilitation of pediatric acquired brain injury. Arch Phys Med Rehabil. 2015 Apr;96(4 Suppl):S129-37. doi: 10.1016/j.apmr.2014.10.013. Epub 2014 Nov 6.
    Results Reference
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    PubMed Identifier
    31078616
    Citation
    Elbanna ST, Elshennawy S, Ayad MN. Noninvasive Brain Stimulation for Rehabilitation of Pediatric Motor Disorders Following Brain Injury: Systematic Review of Randomized Controlled Trials. Arch Phys Med Rehabil. 2019 Oct;100(10):1945-1963. doi: 10.1016/j.apmr.2019.04.009. Epub 2019 May 10.
    Results Reference
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    PubMed Identifier
    28320187
    Citation
    Estraneo A, Pascarella A, Moretta P, Masotta O, Fiorenza S, Chirico G, Crispino E, Loreto V, Trojano L. Repeated transcranial direct current stimulation in prolonged disorders of consciousness: A double-blind cross-over study. J Neurol Sci. 2017 Apr 15;375:464-470. doi: 10.1016/j.jns.2017.02.036. Epub 2017 Feb 17.
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    Citation
    Giacino JT, Whyte J, Bagiella E, Kalmar K, Childs N, Khademi A, Eifert B, Long D, Katz DI, Cho S, Yablon SA, Luther M, Hammond FM, Nordenbo A, Novak P, Mercer W, Maurer-Karattup P, Sherer M. Placebo-controlled trial of amantadine for severe traumatic brain injury. N Engl J Med. 2012 Mar 1;366(9):819-26. doi: 10.1056/NEJMoa1102609.
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    Citation
    Hameed MQ, Dhamne SC, Gersner R, Kaye HL, Oberman LM, Pascual-Leone A, Rotenberg A. Transcranial Magnetic and Direct Current Stimulation in Children. Curr Neurol Neurosci Rep. 2017 Feb;17(2):11. doi: 10.1007/s11910-017-0719-0.
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    Citation
    Palm U, Segmiller FM, Epple AN, Freisleder FJ, Koutsouleris N, Schulte-Korne G, Padberg F. Transcranial direct current stimulation in children and adolescents: a comprehensive review. J Neural Transm (Vienna). 2016 Oct;123(10):1219-34. doi: 10.1007/s00702-016-1572-z. Epub 2016 May 12.
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    Saleem GT, Ewen JB, Crasta JE, Slomine BS, Cantarero GL, Suskauer SJ. Single-arm, open-label, dose escalation phase I study to evaluate the safety and feasibility of transcranial direct current stimulation with electroencephalography biomarkers in paediatric disorders of consciousness: a study protocol. BMJ Open. 2019 Aug 10;9(8):e029967. doi: 10.1136/bmjopen-2019-029967.
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    Safety and Efficacy of tDCS in Pediatric DoC

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