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Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease, which is a group of neurological disorders that selectively affect motor neurons, the cells that control voluntary muscles of the body. The disorder causes muscle weakness and atrophy throughout the body due to the degeneration of the upper and lower motor neurons. Current drugs approved for ALS treatment only modestly slow disease progression.
Transcranial direct current stimulation (tDCS) is a non-invasive technique, which has been demonstrated to modulate cerebral excitability in several neurodegenerative disorders and modulate intracortical connectivity measures.
In this randomized, double-blind, sham-controlled study, the investigators will evaluate whether a two-weeks' treatment with bilateral motor cortex anodal tDCS and spinal cathodal tDCS can improve symptoms in patients with amyotrophic lateral sclerosis and modulate intracortical connectivity, at short and long term.
Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease, which is a group of neurological disorders that selectively affect motor neurons, the cells that control voluntary muscles of the body. The disorder causes muscle weakness and atrophy throughout the body due to the degeneration of the upper and lower motor neurons. Current drugs approved for ALS treatment only modestly slow disease progression.
Transcranial direct current stimulation (tDCS) is a non-invasive technique, which has been demonstrated to modulate cerebral excitability in several neurodegenerative disorders and modulate intracortical connectivity measures.
In this randomized, double-blind, sham-controlled study, the investigators will evaluate whether a two-weeks' treatment with bilateral motor cortex anodal tDCS and spinal cathodal tDCS can improve symptoms in patients with amyotrophic lateral sclerosis and modulate intracortical connectivity, at short and long term.
Subjects will be randomized in two groups, one receiving a 10 day (5 days/week for 2 weeks) treatment with anodal bilateral motor cortex tDCS and cathodal spinal tDCS and the other receiving sham stimulation with identical parameters. After the intervention, patients will be reassessed with a clinical and neurophysiological evaluation at 2 weeks, 2 months and 6 months after treatment. Furthermore, blood neurofilaments will be measured at each time point.
Clinical evaluation will include the ALSFRS-R, ALSAQ-40, CBI, EQ-5D-5L, muscle strength evaluated with the MRC scale.
Neurophysiological evaluation will include measures of intracortical connectivity, evaluated with transcranial magnetic stimulation (TMS) as short interval intracortical inhibition (SICI-ICF), long interval intracortical inhibition (LICI), short interval intracortical facilitation (SICF).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Real tDCS | Experimental | 10 days anodal bilateral motor cortex and cathodal spinal tDCS |
|
| Sham tDCS | Placebo Comparator | 10 days sham bilateral motor cortex and sham spinal tDCS |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Anodal bilateral motor cortex and cathodal spinal tDCS | Device | 10 sessions of anodal bilateral motor cortex and cathodal spinal transcranial direct current stimulation (5 days/week for 2 weeks) |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Muscle Strength From Baseline | A megascore is obtained by summing scores of single muscles (shoulder abductors, elbow flexors and extensors, wrist flexors, thumb opponent, hip flexors, knee flexors and extensors, and ankle dorsiflexors and extensors on both sides) manually evaluated according to the Medical Research Council (MRC) scale, which ranges from 0 (no movement) to 5 (normal contraction). The score for each muscle is summed, with scores ranging from 100 (no impairment) to 0 (most severe impairment). | Baseline - 2 weeks - 2 months - 6 months |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Short-interval Intracortical Inhibition (SICI) From Baseline | By using transcranial magnetic stimulation (TMS), the investigators will evaluate the effects of tDCS on short-interval intracortical inhibition (SICI) from baseline | Baseline - 2 weeks - 2 months - 6 months |
| Change in the ALSFRS-R Score From Baseline |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Barbara Borroni, MD | Azienda Ospedaliera Spedali Civili, Brescia | Principal Investigator |
| Alberto Benussi, MD | Università degli Studi di Brescia | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| AO Spedali Civili | Brescia | BS | 25100 | Italy |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 17221883 | Background | Quartarone A, Lang N, Rizzo V, Bagnato S, Morgante F, Sant'angelo A, Crupi D, Battaglia F, Messina C, Girlanda P. Motor cortex abnormalities in amyotrophic lateral sclerosis with transcranial direct-current stimulation. Muscle Nerve. 2007 May;35(5):620-4. doi: 10.1002/mus.20737. | |
| 27866120 | Background | Lefaucheur JP, Antal A, Ayache SS, Benninger DH, Brunelin J, Cogiamanian F, Cotelli M, De Ridder D, Ferrucci R, Langguth B, Marangolo P, Mylius V, Nitsche MA, Padberg F, Palm U, Poulet E, Priori A, Rossi S, Schecklmann M, Vanneste S, Ziemann U, Garcia-Larrea L, Paulus W. Evidence-based guidelines on the therapeutic use of transcranial direct current stimulation (tDCS). Clin Neurophysiol. 2017 Jan;128(1):56-92. doi: 10.1016/j.clinph.2016.10.087. Epub 2016 Oct 29. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Real tDCS | 10 days anodal bilateral motor cortex and cathodal spinal tDCS Anodal bilateral motor cortex and cathodal spinal tDCS: 10 sessions of anodal bilateral motor cortex and cathodal spinal transcranial direct current stimulation (5 days/week for 2 weeks) |
| FG001 | Sham tDCS | 10 days sham bilateral motor cortex and sham spinal tDCS Sham bilateral motor cortex and sham spinal tDCS: 10 sessions of sham bilateral motor cortex and sham spinal transcranial direct current stimulation (5 days/week for 2 weeks) |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention (2 Weeks) |
| |||||||||||||
| Follow-up (6 Months) |
|
Baseline analysis are reported for 30 participants who completed the first intervention.
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| ID | Title | Description |
|---|---|---|
| BG000 | Real tDCS | 10 days anodal bilateral motor cortex and cathodal spinal tDCS Anodal bilateral motor cortex and cathodal spinal tDCS: 10 sessions of anodal bilateral motor cortex and cathodal spinal transcranial direct current stimulation (5 days/week for 2 weeks) |
| BG001 | Sham tDCS |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in Muscle Strength From Baseline | A megascore is obtained by summing scores of single muscles (shoulder abductors, elbow flexors and extensors, wrist flexors, thumb opponent, hip flexors, knee flexors and extensors, and ankle dorsiflexors and extensors on both sides) manually evaluated according to the Medical Research Council (MRC) scale, which ranges from 0 (no movement) to 5 (normal contraction). The score for each muscle is summed, with scores ranging from 100 (no impairment) to 0 (most severe impairment). | Posted | Mean | Standard Deviation | units on a scale | Baseline - 2 weeks - 2 months - 6 months |
|
6 Months follow-up
Adverse event has been defined as any untoward or unfavorable medical occurrence in a participant, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the participant's participation in the research, whether or not considered related to the participant's participation in the research.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Real tDCS | 10 days anodal bilateral motor cortex and cathodal spinal tDCS Anodal bilateral motor cortex and cathodal spinal tDCS: 10 sessions of anodal bilateral motor cortex and cathodal spinal transcranial direct current stimulation (5 days/week for 2 weeks) |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Pneumonia | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Prof. Barbara Borroni | Spedali Civili di Brescia | +39 0303995631 | bborroni@inwind.it |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | May 5, 2017 | Nov 4, 2019 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D000690 | Amyotrophic Lateral Sclerosis |
| D016472 | Motor Neuron Disease |
| ID | Term |
|---|---|
| D013118 | Spinal Cord Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D019636 | Neurodegenerative Diseases |
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| Sham bilateral motor cortex and sham spinal tDCS | Device | 10 sessions of sham bilateral motor cortex and sham spinal transcranial direct current stimulation (5 days/week for 2 weeks) |
|
Change in the ALS Functional Rating Scale (ALSFRS-R) score from baseline. The ALSFRS provides a physician-generated estimate of the patient's degree of functional impairment, which can be evaluated serially to objectively assess any response to treatment or progression of disease. The ALSFRS includes ten questions that rate the patients level of functional impairment in performing one of ten common tasks. Each task is rated on a five-point scale from 0 (can't do) to 4 (normal ability). Individual item scores are summed to produce a reported score of between 40 (no impairment) and 0 (severe impairment). |
| Baseline - 2 weeks - 2 months - 6 months |
| Change of Quality of Life From Baseline: ALSAQ-40 Scale | Change of quality of life from baseline evaluated with the ALSAQ-40 scale. The Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ) is a patient self-report health status scale. The ALSAQ is specifically used to measure the subjective well-being of patients with amyotrophic lateral sclerosis. There are 40 items/questions with 5 discrete scales: physical mobility (10 items), activities of daily living and independence (10 items), eating and drinking (3 items), communication (7 items), emotional reactions (10 items). Patients are asked to think about the difficulties they may have experienced during the last two weeks (e.g. I have found it difficult to feed myself). Patients are asked to indicate the frequency of each event by selecting one of 5 options (Likert scale): never/rarely/sometimes/often/always or cannot do at all. The total ranges from 0 (no impairment) to 160 (severe impairment). | Baseline - 2 weeks - 2 months - 6 months |
| Change of Quality of Life From Baseline: EQ-5D-5L Scale | Change of quality of life from baseline evaluated with the EQ-5D-5L scale. The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. The scale ranges from 5 (no impairment) to 25 (severe impairment). | Baseline - 2 weeks - 2 months - 6 months |
| Change of Quality of Life From Baseline: EQ-VAS Scale | Change of quality of life from baseline evaluated with the EQ-VAS scale. The EQ VAS records the patient's self-rated health on a vertical visual analogue scale, where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'. The VAS can be used as a quantitative measure of health outcome that reflect the patient's own judgement. The scale ranges from 0 (severe impairment) to 100 (no impairment). | Baseline - 2 weeks - 2 months - 6 months |
| Change in Caregiver Burden (CBI) | Change of quality of life from baseline evaluated with the CBI scale. The CBI scale is 24- item scale designed to assess the experience of caregivers of older people. The multidimensional instrument assesses five domains of burden (time-dependence, developmental, physical, social, and emotional). Items are scored on a 4-point scale, ranging from "not at all descriptive" to "very descriptive". The scale ranges from 0 (no impairment) to 96 (severe impairment). | Baseline - 2 weeks - 2 months - 6 months |
| Change Intracortical Facilitation (ICF) From Baseline | By using transcranial magnetic stimulation (TMS), the investigators will evaluate the effects of tDCS on intracortical facilitation (ICF) from baseline | Baseline - 2 weeks - 2 month - 6 months |
| 25843898 | Background | Menon P, Geevasinga N, Yiannikas C, Howells J, Kiernan MC, Vucic S. Sensitivity and specificity of threshold tracking transcranial magnetic stimulation for diagnosis of amyotrophic lateral sclerosis: a prospective study. Lancet Neurol. 2015 May;14(5):478-84. doi: 10.1016/S1474-4422(15)00014-9. Epub 2015 Apr 3. |
| 21840887 | Background | Burrell JR, Kiernan MC, Vucic S, Hodges JR. Motor neuron dysfunction in frontotemporal dementia. Brain. 2011 Sep;134(Pt 9):2582-94. doi: 10.1093/brain/awr195. Epub 2011 Aug 11. |
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10 days sham bilateral motor cortex and sham spinal tDCS Sham bilateral motor cortex and sham spinal tDCS: 10 sessions of sham bilateral motor cortex and sham spinal transcranial direct current stimulation (5 days/week for 2 weeks) |
| BG002 | Total | Total of all reporting groups |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Disease Duration | Mean | Standard Deviation | years |
|
| OG001 | Sham tDCS | 10 days sham bilateral motor cortex and sham spinal tDCS Sham bilateral motor cortex and sham spinal tDCS: 10 sessions of sham bilateral motor cortex and sham spinal transcranial direct current stimulation (5 days/week for 2 weeks) |
|
|
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| Secondary | Change in Short-interval Intracortical Inhibition (SICI) From Baseline | By using transcranial magnetic stimulation (TMS), the investigators will evaluate the effects of tDCS on short-interval intracortical inhibition (SICI) from baseline | Posted | Mean | Standard Deviation | millivolts | Baseline - 2 weeks - 2 months - 6 months |
|
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|
|
| Secondary | Change in the ALSFRS-R Score From Baseline | Change in the ALS Functional Rating Scale (ALSFRS-R) score from baseline. The ALSFRS provides a physician-generated estimate of the patient's degree of functional impairment, which can be evaluated serially to objectively assess any response to treatment or progression of disease. The ALSFRS includes ten questions that rate the patients level of functional impairment in performing one of ten common tasks. Each task is rated on a five-point scale from 0 (can't do) to 4 (normal ability). Individual item scores are summed to produce a reported score of between 40 (no impairment) and 0 (severe impairment). | Posted | Mean | Standard Deviation | units on a scale | Baseline - 2 weeks - 2 months - 6 months |
|
|
|
|
| Secondary | Change of Quality of Life From Baseline: ALSAQ-40 Scale | Change of quality of life from baseline evaluated with the ALSAQ-40 scale. The Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ) is a patient self-report health status scale. The ALSAQ is specifically used to measure the subjective well-being of patients with amyotrophic lateral sclerosis. There are 40 items/questions with 5 discrete scales: physical mobility (10 items), activities of daily living and independence (10 items), eating and drinking (3 items), communication (7 items), emotional reactions (10 items). Patients are asked to think about the difficulties they may have experienced during the last two weeks (e.g. I have found it difficult to feed myself). Patients are asked to indicate the frequency of each event by selecting one of 5 options (Likert scale): never/rarely/sometimes/often/always or cannot do at all. The total ranges from 0 (no impairment) to 160 (severe impairment). | Posted | Mean | Standard Deviation | units on a scale | Baseline - 2 weeks - 2 months - 6 months |
|
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| Secondary | Change of Quality of Life From Baseline: EQ-5D-5L Scale | Change of quality of life from baseline evaluated with the EQ-5D-5L scale. The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. The scale ranges from 5 (no impairment) to 25 (severe impairment). | Posted | Mean | Standard Deviation | units on a scale | Baseline - 2 weeks - 2 months - 6 months |
|
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| Secondary | Change of Quality of Life From Baseline: EQ-VAS Scale | Change of quality of life from baseline evaluated with the EQ-VAS scale. The EQ VAS records the patient's self-rated health on a vertical visual analogue scale, where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'. The VAS can be used as a quantitative measure of health outcome that reflect the patient's own judgement. The scale ranges from 0 (severe impairment) to 100 (no impairment). | Posted | Mean | Standard Deviation | units on a scale | Baseline - 2 weeks - 2 months - 6 months |
|
|
|
|
| Secondary | Change in Caregiver Burden (CBI) | Change of quality of life from baseline evaluated with the CBI scale. The CBI scale is 24- item scale designed to assess the experience of caregivers of older people. The multidimensional instrument assesses five domains of burden (time-dependence, developmental, physical, social, and emotional). Items are scored on a 4-point scale, ranging from "not at all descriptive" to "very descriptive". The scale ranges from 0 (no impairment) to 96 (severe impairment). | Posted | Mean | Standard Deviation | units on a scale | Baseline - 2 weeks - 2 months - 6 months |
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| Secondary | Change Intracortical Facilitation (ICF) From Baseline | By using transcranial magnetic stimulation (TMS), the investigators will evaluate the effects of tDCS on intracortical facilitation (ICF) from baseline | Posted | Mean | Standard Deviation | millivolts | Baseline - 2 weeks - 2 month - 6 months |
|
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| 0 |
| 20 |
| 4 |
| 20 |
| 0 |
| 20 |
| EG001 | Sham tDCS | 10 days sham bilateral motor cortex and sham spinal tDCS Sham bilateral motor cortex and sham spinal tDCS: 10 sessions of sham bilateral motor cortex and sham spinal transcranial direct current stimulation (5 days/week for 2 weeks) | 0 | 10 | 2 | 10 | 0 | 10 |
| Respiratory Failure | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Worsening of Global Clinical Conditions | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
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| D057177 | TDP-43 Proteinopathies |
| D009468 | Neuromuscular Diseases |
| D057165 | Proteostasis Deficiencies |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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