Administrative information
Title {1} | Efficacy and auditory biomarker analysis of fronto-temporal transcranial direct current stimulation (tDCS) in cognitive impairment associated with recent-onset schizophrenia: study protocol for a multicenter randomized double-blind sham-controlled trial Short title: tDCS for Cognitive Impairment Associated With Recent-onset Schizophrenia (STICOG) Original French title: Efficacité et tolérance de la stimulation électrique transcrânienne fronto-temporale gauche à courant continu (tDCS) comme traitement du déficit cognitif chez les sujets atteints de schizophrénie débutante : un essai multicentrique, randomisé, contrôlé. |
Trial registration {2a and 2b} | Clinicaltrials.gov registration number: NCT05440955, first posted on July 1st, 2022 |
Protocol version {3} | version 0.2 on June 7th 15th, 2021, substantial modification n°1 |
Funding {4} | The French Ministry of Health, DGOS, PHRC IR Interrégional 2020 |
Author details {5a} | 1 Univ. Grenoble Alpes, Inserm, CHU Grenoble Alpes, Grenoble Institut Neurosciences, 38000 Grenoble, France 2 Adult Psychiatry Department CHU Grenoble Alpes 38000 Grenoble, France 3 Early Intervention Psychiatry Department, CH Alpes-Isère, F-38000 Saint-Egrève, France. 4 CERMEP-Imagerie du vivant, Lyon, France. 5 Psychiatry Department, University Hospital Saint-Etienne. INSERM, U1028; CNRS, UMR5292; Lyon Neuroscience Research Center, PSYR2 Team, F-69000, Lyon, France. 6 Centre Hospitalier le Vinatier, F-69500 Bron, France. 7 CHU Saint-Étienne, University Department of Psychiatry and Addiction, 42055 Saint-Étienne Cedex 2, France TAPE Laboratory, EA7423, Jean Monnet University, Saint-Étienne, France 8 SUR-CL3R-PEPS, Centre Hospitalier Le Vinatier, PSYR2 team, Bat 416 – 1st floor; 95 boulevard Pinel, 69678, F-69500, Bron cedex, France. INSERM, U1028; CNRS, UMR5292; Lyon Neuroscience Research Center, PSYR2 Team, F-69000, Lyon, France. Lyon 1 University, F-69000, Villeurbanne, France. 9 Univ. Grenoble Alpes, UMS IRMaGe CHU Grenoble, 38000 Grenoble, France. 10 Psychiatry Department, University Hospital Saint-Etienne, France. 11 Service de Radiologie, CHU de Saint Etienne TAPE EA 7423, Université Jean Monnet, Saint Etienne. 12 Centre Hospitalier Le Vinatier, PSYR2 team, Bat 416 – 1st floor; 95 boulevard Pinel, 69678, F-69500, Bron cedex, France. INSERM, U1028; CNRS, UMR5292; Lyon Neuroscience Research Center, PSYR2 Team, F-69000, Lyon, France. Lyon 1 University, F-69000, Villeurbanne, France. Université Jean Monnet Saint Etienne, F-42000, Saint Etienne, France. |
Name and contact information for the trial sponsor {5b} | Julien Colombat, Clinical Project Manager Direction de la Recherche Clinique et de l’Innovation, CHU Grenoble Alpes, DRCI, CS10217, 38043 Grenoble Cedex 9 Tél : +33 4 76 76 56 09 jcolombat@chu-grenoble.fr / accueilrecherche@chu-grenoble.fr |
Role of sponsor {5c} | The study sponsor and the funder of the study had no role in the study design, and will not have any role during collection, analyses and interpretation of the data, decision to submit results and writing of study reports. |
Introduction
Background and rationale {6a}
Objectives {7}
Objective 1 (main objective) and hypothesis
Secondary objectives and hypotheses
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Objective 2a is to compare the long-term efficacy of active tDCS versus sham on global cognitive impairment in patients with recent-onset schizophrenia at 3-month follow-up.
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Objective 2b is to compare the efficacy of active tDCS versus sham on different cognitive aspects (processing speed, attention/vigilance, working memory, verbal learning, visual learning, problem-solving, emotional awareness) measured with the MCCB in patients with recent-onset schizophrenia at 1- and 3-month follow-up.
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Objective 2c is to compare the efficacy of active tDCS versus sham on different clinical aspects of schizophrenia (hallucinations, positive, negative, disorganization, depression, grandiosity/excitement, manic symptoms, and subjective experience of cognitive impairment) measured with validated symptom rating scales in patients with recent-onset schizophrenia at the end of the tDCS treatment and at 1- and 3-month follow-up.
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Objective 2d is to compare the efficacy of active tDCS versus sham on the outcome (functioning, quality of life) measured with validated rating scales in patients with recent-onset schizophrenia at the end of the tDCS treatment and at 1- and 3-month follow-up.
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Objective 3 is to compare the clinical tolerance of active tDCS versus sham measured with adverse effects questionnaires in patients with recent-onset schizophrenia at the end of the tDCS treatment.
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Objective 4a is to assess how differences in EAP mechanisms modulate individual cognitive benefits from active tDCS measured with a range of EAP measures in patients with recent-onset schizophrenia at 1-month follow-up.
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Objective 4b is to evaluate whether there are changes in EAP measures in patients associated with cognitive improvement after active tDCS at 1-month follow-up.
Trial design {8}
Methods: Participants, interventions, and outcomes
Study setting {9}
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Centre Hospitalo Universitaire Grenoble Alpes, Department of Adult Psychiatry, Grenoble (10 participants). Neuroimaging platform: IRMaGE.
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Centre Hospitalier Alpes-Isère, Department of Psychiatry, Saint-Egrève (10 participants). Neuroimaging platform: IRMaGE.
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Centre Hospitalier Le Vinatier, Department of Psychiatry, Bron (20 participants). Neuroimaging platform: CERMEP.
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Centre Hospitalo-Universitaire de Saint-Etienne, Department of Psychiatry, Saint-Etienne (20 participants). Neuroimaging platform: IRMAS.
Eligibility criteria {10}
Who will take informed consent? {26a}
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Interventions
Intervention description {11a}
Explanation for the choice of comparators {6b}
Criteria for discontinuing or modifying allocated interventions {11b}
Strategies to improve adherence to interventions {11c}
Relevant concomitant care permitted or prohibited during the trial {11d}
Provisions for post-trial care {30}
Outcomes {12}
Primary outcome
Secondary outcome
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Schizophrenia symptoms will be assessed using the PANSS (Positive and Negative Syndrome Scale) total score. In addition, PANSS subscores for positive, negative, disorganization, depression, and grandiosity/excitement symptoms will be used as outcomes [32].
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Auditory hallucinations, one of the key symptoms of schizophrenia, will be assessed using the AHRS (Auditory Hallucination Rating Scale) [33].
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Negative symptoms will be additionally assessed using the Brief Negative Symptom Scale (BNSS) [34].
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Depressive symptoms will be assessed using the Calgary Depression Scale for Schizophrenia (CDSS) total score [30].
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Global symptom severity and treatment response will be assessed using the Clinical Global Impressions Scale (CGI) total score [35].
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Cognitive insight abilities will be assessed using the Beck Cognitive Insight Scale total score [36].
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Perceptual anomalies will be assessed using the self-rated Cardiff Anomalous Perceptions Scale (CAPS) total score [37].
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Subjective experience of negative symptoms will be assessed using the self-rated Self-evaluation of Negative Symptoms (SNS) total score [38].
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Subjective experiences of cognitive impairment will be assessed using the self-rated Subjective Scale To Investigate Cognition in Schizophrenia (SSTICS) total score [39].
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Correlations (z-scores) between left prefrontal and temporal cortical areas (i.e., areas stimulated with tDCS) measured with resting-state functional magnetic resonance imaging (MRI).
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Spectral power (dB) and inter-assay coherence (%) in gamma frequency (40-Hz) during specific auditory paradigms (auditory steady-state, oddball, tone-matching) measured with electroencephalography (EEG).
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GABA and glutamate levels (mM) within left prefrontal and temporal cortical areas measured with resting-state Magnetic Resonance Spectroscopy (MRS)
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radiotracer binding potential on GABA-A receptors (Binding Potential) within left prefrontal and temporal cortical areas measured with resting-state [11C]flumazenil positron emission tomography MRI (PET-MRI).
Participant timeline {13}
Sample size {14}
Recruitment {15}
Assignment of interventions: allocation
Sequence generation {16a}
Concealment mechanism {16b}
Implementation {16c}
Assignment of interventions: blinding
Who will be blinded {17a}
Procedure for unblinding if needed {17b}
Data collection and management
Plans for assessment and collection of outcomes {18a}
Psychometric outcomes measures
MATRICS Consensus Cognitive Battery total score (MCCB)
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Processing speed: Trail Making Test- Part A; Brief Assessment of Cognition in Schizophrenia- symbol coding subtest; Category fluency test animal naming
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Attention/vigilance: Continuous Performance Test- Identical Pairs version.
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Working memory: Wechsler Memory Scale, 3rd ed., spatial span subtest; Letter-Number Span test
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Verbal learning: Hopkins Verbal Learning Test-Revised.
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Visual learning: Brief Visuospatial Memory Test-Revised.
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Problem-solving: Neuropsychological Assessment Battery-mazes subtest.
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Emotional awareness: Mayer-Salovey-Caruso Emotional Intelligence Test.
Positive and Negative Syndrome Scale (PANSS)
Auditory Hallucinations Rating Scale (AHRS)
Brief Negative Symptom Scale (BNSS)
Calgary Depression Scale for Schizophrenia (CDSS)
Clinical Global Impression (CGI)
Beck Cognitive Insight Scale (BCIS)
Cardiff Anomalous Perceptions Scale (CAPS)
Self-evaluation of Negative Symptoms (SNS)
Subjective Scale To Investigate Cognition in Schizophrenia (SSTICS)
Questionnaire of the Functional Remission Observatory Group in Schizophrenia (FROGS)
Schizophrenia Quality of Life Questionnaire Short Form (S-QoL 18)
tDCS adverse effects questionnaire (tDCS-AEQ)
Neurobiological outcomes measures
Electroencephalography
Magnetic resonance imaging
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aMRI: A few minutes of anatomical MRI sequence (T1-weighted 3D MP-RAGE) will be used for spatial normalization in stereotactic space, anatomical segmentation and parcellation, and extraction of time activity curves by regions during the next acquisitions. Cerebral areas of each participant will be mapped by deformations of standard atlases on the T1 image of the subject.
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rsfMRI: A 15-min resting-state functional MRI sequence will be acquired in axial multislice using traditional gradient echo sequences with a maximum temporal resolution of 3 s. The acquisition will be used to establish maps of the activation and functional connectivity of the fronto-temporal cortical network. A short acquisition to characterize the local inhomogeneities of the B0 magnetic field will be included in order to correct the geometrical distortions they induce.
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MRS: A 30-min acquisition of monovoxel magnetic resonance spectroscopy with GABA editing will be carried out. Two large voxels of interest (left prefrontal and temporal cortices, dimension 3×3×3 cm3 each) will be targeted based on T1 anatomical images. The acquisition will be performed by a "MEGA-PRESS" MRI sequence, which simultaneously removes the water signal and captures the spectral resonance of GABA (γ-CH2, 3 ppm) to estimate its relative concentration (mM) to a stable reference peak. Parameters will be the following: TR/TE = 2000/68 (ms), water signal suppression, 320 excitations divided into 80 dynamics with editing pulse alternately applied at 7.46 and 1.90 ppm between dynamics, phase cycling on 8 excitations per dynamic. Spectra without water signal suppression will also be acquired as a reference for pre-processing.
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PET-MRI: A positron emission tomography acquisition with the GABA marker ([11C]flumazenil) will be carried out simultaneously to the MRI sequences described above (PET-MRI). A preliminary interview with a nuclear physician will be performed on the day of the PET-MRI examination. The PET scanner, associated with the MRI imager, is a Biograph mMR, Siemens Healthcare, with an internal tunnel diameter of 60 cm and a useful field of view of 50×50×50 cm2 in MRI and 59×59×26 cm2 in PET. The PET images produced are volumes of 127 slices of 2mm thickness. The spatial resolution (NEMA standard) is 4.3 mm (total width at half height, FWHM) and isotropic at the center of the field of view. The combination of PET and MRI scans will, after coregistration, improve the spatial resolution and thus refine the data analysis. PET acquisition is performed simultaneously with the MRI sequences described above. PET-MRI requires the installation of a venous catheter by a medical electroradiology manipulator. In our protocol, carbon-11-labeled flumazenil will be synthesized only once per participant. After MRI tracking and attenuation correction sequences have been performed, the injection of the [11C]flumazenil 2.5 MBq/kg bolus will be performed at the same time as the start of the PET recording. Dynamic PET data will be recorded 60 min after the injection of [11C]flumazenil. Of note, only one of the investigation centers (Centre Hospitalier Le Vinatier) has a PET-MRI device and will thus participate in the PET-MRI acquisition.
Plans to promote participant retention and complete follow-up {18b}
Data management {19}
Confidentiality {27}
Statistical methods
Statistical analysis plan
Statistical methods for primary and secondary outcomes {20a}
Main outcome
Secondary outcomes
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Outcome 2a: the percentage of “responders” and the number of responders at 3-month follow-up will be compared using the same tests as for the main outcome.
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Outcomes 2b: the changes from baseline to endpoints in MCCB cognitive domains subscores will be analyzed using mixed effects regression models with group (active or sham) and time (before tDCS, 1-month follow-up, 3-month follow-up) as independent variables.
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Outcomes 2c: the changes from baseline to endpoints in clinical symptom measures will be analyzed using mixed effects regression models with group (active or sham) and time (before tDCS, after tDCS, 1-month follow-up, 3-month follow-up) as independent variables.
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Outcomes 2d: the changes from baseline to endpoints in schizophrenia outcome will be analyzed using mixed effects regression models with group (active or sham) and time (before tDCS, 1-month follow-up, 3-month follow-up) as independent variables.
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Outcome 3: tDCS tolerance questionnaire scores measured after tDCS will be compared between the active tDCS and sham tDCS groups using mean comparison tests.
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Outcome 4a: the difference at baseline between responders and non-responders in EAP measures will be analyzed using mixed effects regression models with cognitive improvement status (responder or non-responder) and group (active or sham) as independent variables.
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Outcome 4b: the changes from baseline to 1-month follow-up in EAP measures will be analyzed using mixed effects regression models with cognitive improvement status (responder or non-responder), group (active or sham), and time (before tDCS and 1-month follow-up) as independent variables.
Additional note on preprocessing of neurobiological data (outcomes 4a and 4b}
Electroencephalography
Magnetic resonance imaging
Interim analyses {21b}
Methods for additional analyses (e.g., subgroup analyses) {20b}
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
Plans to give access to the full protocol, participant level-data and statistical code (31c}
Oversight and monitoring
Composition of the coordinating center and trial steering committee {5d}
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Principal investigator: Dr. Clément Dondé
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Methodology:
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Scientific advisory: Dr. Julien Bastin, Dr. Jérôme Brunelin
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Trial methodology and study coordination: Dr. Clément Dondé, Prof. Mircea Polosan
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Statistical analyses: Dr. Julien Bastin
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Quality control and study safety monitoring: Direction de la Recherche Clinique et de l’Innovation, CHU Grenoble Alpes, DRCI, CS10217, 38043 Grenoble Cedex 9
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Imaging: Dr. Laurent Lamalle, Dr. Inès Troprès, Dr. Nicolas Costes, Dr. Julien Bastin
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Data management: Mrs. Blandine Chanteloup