Non Invasive Vagus Nerve Stimulation in Cerebral Palsy (BOOSTTVNS)

NCT ID: NCT06372028

Last Updated: 2024-04-17

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: NA
• Total Enrollment: 44 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-04-15
• Study Completion Date: 2026-05-14

Brief Summary

The present study aims to assess, through a randomized controlled trial (RCT), the efficacy of transcutaneous Vagus Nerve Stimulation (tVNS) in enhancing the functional changes due to an intensive motor training in children and adolescents with Cerebral Palsy (CP). Particularly, in two different groups active or sham tVNS will be paired with the Hand-Arm Bimanual Intensive Therapy Including Lower Extremities (HABIT-ILE) and we will assess the effects on the upper limbs motor ability and daily functioning in 6 to 17 years old patients with CP having mild-to moderate upper limb deficits. The investigators hypothesized that, thanks to the intensive bimanual training, both the active and the sham group will improve in motor functioning. However, taking into account that tVNS has the potential to facilitate in a bottom-up way neural plasticity, particularly in chronic disease conditions, the investigators hypothesized that active tVNS might improve in a greater and more lasting extent than sham tVNS the motor functioning. Moreover, as suggested by previous studies investigating the effect of non-invasive brain stimulation (NIBS) in paediatric population, the investigators expected that the treatment will be safe and well tolerated. Such a result would encourage the use of NIBS to boost the rehabilitative training of motor abilities in children and adolescents with CP.

Detailed Description

This represents one of the two RCTs of the project "Bottom-up and tOp-down neuromOdulation of motor plaSTicity in cerebral palsy" (BOOST; FRRB 3438840). The study will be a randomized, sham controlled, pre-test/post-test study involving 44 children and adolescents with CP. Patients will be treated in pairs, with a matching of motor deficit severity, IQ, and age. Each pair will be randomly assigned to the active or to the sham tVNS group, stratifying the pairs between the two groups based on motor deficit severity, IQ, and age. Both groups will undergo a bimanual training in an ecological and highly motivating environment during the application of the tVNS. During the training, starting from a set of proposals the choice of the type of activities to be practiced in each session will be left to patients, boosting the motivational aspect of the training. This will also ensure an individualized and goal directed approach. The therapists will monitor and modify the activities within each pair to ensure that the intervention maintains the quality of the individualized intervention. The positions performed during bimanual tasks and the activities of daily living will be designed to systematically engage postural control of the trunk and lower limbs according to Habit-ILE protocol. The rehabilitation treatment will be carried out for 5 consecutive days for 3h/day for 2 weeks (30 hours of intervention overall). Children and adolescents will be assessed before the start of treatment (T0), immediately after the end of intensive treatment (T1) and three months after the end (T2). The overall RCT will be structured as follows. In the first session prior the beginning of the training (t0), the RCT will include the administration of all clinical assessment measures and the patients will be asked to perform for 10 minutes an ad-hoc computer based Visuomotor task (please refer to the outcome sessions for more detailed description). Then, patients will undergo the 10 days treatment. For each training day, the treatment will last three hours. During the first 75 minutes of treatment the active or sham tVNS (according to the group allocation) will be delivered. Before starting, 20 minutes after and soon after the end of the stimulation the vital parameters will be checked. After the end of the stimulation, patients will be also asked to rate the sensations experienced during the stimulation through Visual Analogue Scales and through child-friendly Likert scales. Then, they will continue the training for the remaining session time without stimulation. Soon after the end of all the training sessions, patients will carry the t1 evaluation. As for the t0 session, this session will include the administration of the clinical assessment measures and execution for 10 minutes of the Visuomotor task. Three months after the end of the training (t2) the follow up assessment will be conducted, following the same exact procedure of t0.

Primary outcomes will include the following clinical measures: the Assisting Hand Assessment (AHA), the Box and Block Test (BBT) and the performance at the Visuomotor task. Secondary outcomes will include the scores at the following tests: the Children's Hand Experience Questionnaire (CHEQ), the Canadian Occupational Performance Measure (COPM), the Gross Motor Function Measure (GMFM-66); the Melbourne Assessment-2 (MA2) scale, the Vineland Adaptive Behavior Scale Version 2 (VABS II), the Pediatric Quality of Life Inventory (PEDS-QL). Vital parameters (the oxygen saturation (SPO2) and the Heart Rate (HR)), and the scores at the questionnaires assessing stimulation- induced sensations will be also checked to assess the safety and the tolerability of the stimulation. Lastly, the feasibility and the acceptability of the training will be assessed by considering, respectively, the number of patients completing the training/the number of sessions for each patient and the response to ad hoc questionnaires for the patients and their guardians.

All primary and secondary outcomes will be collected at each time point, except for the PEDS-QL and VABS II, which will be administered only at T0 and T2. Furthermore, vital parameters and the questionnaires assessing stimulation-induced sensations will be examined during each stimulation session. The acceptability questionnaires will be administered only after the end of the training (t1).

The patients and their guardians, the personnel responsible for conducting the bimanual training and analysing clinical data will be kept blind to the group allocation. Instead, the coordinator of the study, the staff who will apply the tVNS will be "not blind". With respect to the clinical assessment, whenever possible the staff administering and scoring the scales will be blinded to group allocation. Questionnaire scores and neuropsychological tests will not contain personal information about the subjects, who will be identified by an alphanumeric code. All records that contain names or other personal identifiers, such as informed consent forms, will be stored separately from study records identified by code number. In order to uphold the overall quality of the clinical trial, instances of code breaks should be limited to exceptional circumstances, where knowledge of the actual treatment is deemed absolutely necessary for the ongoing management of the patient.

The intensive treatment will take place at IRCCS E. Medea "Associazione La Nostra Famiglia" in Bosisio Parini (Lecco), at Fondazione Mondino IRCCS (Pavia) and at ASST Ospedali Civili di Brescia.

This trial is supported by Fondazione Regionale per la Ricerca Biomedica (Regione Lombardia), project FRRB 3438840 BOOST "Bottom-up and tOp-down neuromOdulation of motor plaSTicity in cerebral palsy"

Conditions

Cerebral Palsy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Active tVNS combined with the training

The active stimulation will be applied through an active electrode placed on the cymba conchae (the auricular branches of the vagus nerve) of the left ear. The intensity will be set based on the individual perceptual threshold, below the perception of pain. The intensity of the stimulation will be gradually increased in order to reach the intensity of stimulation with a ramping-up phase of 30 secs. The tVNS will be applied for the first 75 minutes of the training, every day of the treatment. Before, 20 minutes and 75 minutes after the start of the stimulation SpO2 and HR will be checked. At the end of the stimulation session participants will be asked to report the sensations and possible side effects occurring during tVNS and to rate their feeling on several visual analogue scales and Likert scales. The intensive bimanual training will be administered by following the procedure described in the Detailed Description session, as for the Sham tVNS combined with the training arm.

Group Type: EXPERIMENTAL

transcutaneous vagus nerve stimulation (tVNS)

Intervention Type: DEVICE

tVNS allows the non-invasive stimulation of the Vagus Nerve by delivering electrical pulses to the sensory afferent fibers of the auricular, thick-myelinated, branch of the vagus nerve in the outer ear. TVNS seems to engage the same neural pathways of invasive VNS methods and may provide a novel, bottom-up NIBS method to enhance gamma-aminobutyric acid and Noradrenaline levels, which play a pivotal role in brain plasticity. The stimulation will be performed by using a Conformite Europeenne (CE) marked tVNS device tVNS®E (tVNS, technologies Gesellschaft mit beschränkter Haftung (GMBH), Erlangen, Germany). It consists in a programmable stimulation unit connected to two titan ear electrodes that are mounted on a gel frame, allowing to generate and transfer electric impulses from the stimulation unit to the surface of the skin, where the electrodes are applied.

Sham tVNS combined with the training

The sham stimulation will be applied through an active electrode placed on lobe of the left ear that is free of cutaneous vagal innervations. The stimulation intensity will be set based on the individual perceptual threshold, below the perception of pain. The intensity of the stimulation will be gradually increased in order to reach the intensity of stimulation with a ramping-up phase of 30 secs. The tVNS will be applied for the first 75 minutes of the training, every day of the treatment. Before, 20 minutes and 75 minutes after the start of the stimulation SpO2 and HR will be checked. At the end of the stimulation session participants will be asked to report the sensations and possible side effects occurring during tVNS and to rate their feeling on several visual analogue scales and Likert scales. The intensive bimanual training will be administered by following the procedure described in the Detailed Description session, as for the Active tVNS combined with the training arm.

Group Type: SHAM_COMPARATOR

transcutaneous vagus nerve stimulation (tVNS)

Intervention Type: DEVICE

tVNS allows the non-invasive stimulation of the Vagus Nerve by delivering electrical pulses to the sensory afferent fibers of the auricular, thick-myelinated, branch of the vagus nerve in the outer ear. TVNS seems to engage the same neural pathways of invasive VNS methods and may provide a novel, bottom-up NIBS method to enhance gamma-aminobutyric acid and Noradrenaline levels, which play a pivotal role in brain plasticity. The stimulation will be performed by using a Conformite Europeenne (CE) marked tVNS device tVNS®E (tVNS, technologies Gesellschaft mit beschränkter Haftung (GMBH), Erlangen, Germany). It consists in a programmable stimulation unit connected to two titan ear electrodes that are mounted on a gel frame, allowing to generate and transfer electric impulses from the stimulation unit to the surface of the skin, where the electrodes are applied.

Interventions

transcutaneous vagus nerve stimulation (tVNS)

tVNS allows the non-invasive stimulation of the Vagus Nerve by delivering electrical pulses to the sensory afferent fibers of the auricular, thick-myelinated, branch of the vagus nerve in the outer ear. TVNS seems to engage the same neural pathways of invasive VNS methods and may provide a novel, bottom-up NIBS method to enhance gamma-aminobutyric acid and Noradrenaline levels, which play a pivotal role in brain plasticity. The stimulation will be performed by using a Conformite Europeenne (CE) marked tVNS device tVNS®E (tVNS, technologies Gesellschaft mit beschränkter Haftung (GMBH), Erlangen, Germany). It consists in a programmable stimulation unit connected to two titan ear electrodes that are mounted on a gel frame, allowing to generate and transfer electric impulses from the stimulation unit to the surface of the skin, where the electrodes are applied.

Intervention Type: DEVICE

Eligibility Criteria

Inclusion Criteria

• clinical signs of unilateral or bilateral upper limb deficits (with a difference at least of 25% between more affected and less affected hand at Box and Block test);
• Magnetic Resonance Imaging (MRI) confirmed diagnosis according to Surveillance of Cerebral Palsy (SCPE) criteria;
• Manual Ability Classification System (MACS) level I,II,III;
• Gross Motor Function Classification System (GMFCS) level I,II,III;
• Visual Function Classification System (VFCS) I-II-III;
• Intelligence quotient (IQ) > 50.

Exclusion Criteria

• presence of cochlear implant, cardiac pacemaker, ventriculoperitoneal shunt, neuro-stimulators, clips, fragments or metal splinters in the brain or skull except for titanium;
• treatments for spasticity or functional surgery of the upper limb in the previous 6 months or planned during the duration of the study;
• uncontrolled epileptic seizure in the last 2 years.

• Minimum Eligible Age: 6 Years
• Maximum Eligible Age: 17 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

IRCCS National Neurological Institute "C. Mondino" Foundation

OTHER

Sponsor Role: collaborator

Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia

OTHER

Sponsor Role: collaborator

IRCCS Eugenio Medea

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Scientific Institute, IRCCS E. Medea

Bosisio Parini, Lecco, Italy

Countries

Italy

Facility Contacts

Alessandra Finisguerra

Role: primary

alessandra.finisguerra@lanostrafamiglia.it

+39031877652

Cosimo Urgesi

Role: backup

cosimo.urgesi@lanostrafamiglia.it

References

Vacchini V, Brafa B, Nicotra R, Capelli E, Signorini S, Gasparroni V, Michelutti A, Oldrati V, Galli J, Urgesi C, Cattaneo Z, Fazzi EM, Borgatti R, Finisguerra A, Orcesi S; Boost Working Group. Improving neuroplasticity and Quality of Life in children with Cerebral Palsy: a customized intensive motor training protocol integrating the HABIT-ILE approach. Front Rehabil Sci. 2025 Oct 13;6:1613103. doi: 10.3389/fresc.2025.1613103. eCollection 2025.

Reference Type: DERIVED

PMID: 41158535 (View on PubMed)

Oldrati V, Gasparroni V, Michelutti A, Ciricugno A, Borgatti R, Orcesi S, Fazzi E, Morandi A, Galli J, Piccinini L, Maghini C, Arioli M, Cattaneo Z, Urgesi C, Finisguerra A. Pairing transcutaneous vagus nerve stimulation with an intensive bimanual training in children and adolescents with cerebral palsy: study protocol of a randomized sham-controlled trial. Front Neurol. 2024 Aug 16;15:1441128. doi: 10.3389/fneur.2024.1441128. eCollection 2024.

Reference Type: DERIVED

PMID: 39220734 (View on PubMed)

Other Identifiers

944/A

Identifier Type: -

Identifier Source: org_study_id