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Hereditary spastic paraplegia (HSP) is the group of inherited disorders, characterized by progressive gait disturbance. There is no established therapy. Adrenoleukodystrophy (AMN) is an x-linked hereditary disease. One of its form, the adrenomyeloneuropathy has the same symptoms as HSP. Current therapeutic options for AMN are very limited. Repetitive Transcranial Magnetic Stimulation (rTMS) is a noninvasive method of modulation of brain plasticity. The purpose of this study is to compare the effectiveness of rTMS in improving the HSP- and AMN-related gait disturbance and other symptoms with sham stimulation.
Intervention will include five daily sessions. In each session 1500 magnetic pulses will be administered to each of both primary motor areas for lower extremities. Assessment of gait and of strength and spasticity of lower extremities will be made before and after therapy, as well as two weeks later.
Hereditary spastic paraplegia (HSP) is a group of inherited disorders, characterized by progressive gait disturbance with weakness and spasticity, which predominate in lower extremities. There is no established therapy. Adrenoleukodystrophy (AMN) is an x-linked hereditary disease. One of its form, the adrenomyeloneuropathy has the same symptoms as HSP. Current therapeutic options for AMN are very limited. Repetitive Transcranial Magnetic Stimulation (rTMS), a noninvasive method of modulation of brain plasticity proved to be effective in improving the gait performance in several conditions such as Parkinson Disease, vascular Parkinsonism, partial spinal cord injury and in post-stroke paresis. Previous studies documented also altered cortical excitability in HSP patients.
The purpose of this study is to compare the effectiveness of 10 hertz (Hz) rTMS over the primary motor cortices in improving the gait and strength and spasticity of lower extremities with sham stimulation in HSP and AMN patients.
Intervention will include five daily sessions. In each session 1500 magnetic pulses will be administered to each of both primary motor areas for lower extremities. Assessment of gait and of strength and spasticity of lower extremities will be made before and after therapy, as well as two weeks later.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| active rTMS | Experimental | 10 hertz (Hz) rTMS will be administered over bilateral primary motor areas for the muscles of lower extremities. Therapy will include five daily sessions (on consecutive week days). In every sessions 3000 magnetic pulses of 90% of the resting motor threshold intensity will be elicited. |
|
| Sham rTMS | Sham Comparator | Sham stimulation will mimic the active one except that the stimulating coil will be held perpendicularly to the scalp, which assures similar impression as the active stimulation but prevents that significant magnetic field will reach brain tissue. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| rTMS | Device | high frequency rTMS to induce the long term potentiation of primary motor areas for the muscles of lower extremities |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline Walking Time in 10 Meter Walk Test to the Measurement Taken Directly After rTMS | Change in time of walking barefoot the distance of 10 meters with maximal speed, but safely, between baseline and directly after rTMS. | Before rTMS, directly (on the same day) after rTMS |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Timed up and go Test | Time of standing up from a chair, walking three metres to cross a line drawn 3 meters ahead and going back to sit down on the chair. | Baseline, directly (on the same day) after rTMS and 14 days later |
| Change in Medical Research Council Scale (MRC) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jakub M Antczak, MD | Jagiellonian University Medical College, Department of Neurology | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Jagiellonian University Medical College, Department of Neurology | Krakow | 31503 | Poland |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 19833552 | Result | Rossi S, Hallett M, Rossini PM, Pascual-Leone A; Safety of TMS Consensus Group. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol. 2009 Dec;120(12):2008-2039. doi: 10.1016/j.clinph.2009.08.016. Epub 2009 Oct 14. | |
| 31214256 |
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We recruited 15 patients meeting inclusion criteria. One patient dropped out due to seizure, when he was in active treatment.
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| ID | Title | Description |
|---|---|---|
| FG000 | Active rTMS First, Then Sham rTMS | First intervention: 10 hertz (Hz) rTMS will be administered over bilateral primary motor areas for the muscles of lower extremities. Therapy will include five daily sessions (on consecutive week days). In every sessions 3000 magnetic pulses of 90% of the resting motor threshold intensity will be elicited. The washout will last at least one month. Second intervention: Sham stimulation will mimic the active one except that the stimulating coil will be held perpendicularly to the scalp, which assures similar impression as the active stimulation but prevents that significant magnetic field will reach brain tissue. rTMS: high frequency rTMS to induce the long term potentiation of primary motor areas for the muscles of lower extremities |
| FG001 | Sham rTMS, Then Active rTMS | First intervention: Sham stimulation will mimic the active one except that the stimulating coil will be held perpendicularly to the scalp, which assures similar impression as the active stimulation but prevents that significant magnetic field will reach brain tissue. The washout will last at least one month. Second intervention: 10 hertz (Hz) rTMS will be administered over bilateral primary motor areas for the muscles of lower extremities. Therapy will include five daily sessions (on consecutive week days). In every sessions 3000 magnetic pulses of 90% of the resting motor threshold intensity will be elicited. rTMS: high frequency rTMS to induce the long term potentiation of primary motor areas for the muscles of lower extremities |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Active rTMS, Then Sham rTMS | First intervention: 10 hertz (Hz) rTMS will be administered over bilateral primary motor areas for the muscles of lower extremities. Therapy will include five daily sessions (on consecutive week days). In every sessions 3000 magnetic pulses of 90% of the resting motor threshold intensity will be elicited. The washout period will last at least one month. Second intervention: Sham stimulation will mimic the active one except that the stimulating coil will be held perpendicularly to the scalp, which assures similar impression as the active stimulation but prevents that significant magnetic field will reach brain tissue. rTMS: high frequency rTMS to induce the long term potentiation of primary motor areas for the muscles of lower extremities |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| 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 From Baseline Walking Time in 10 Meter Walk Test to the Measurement Taken Directly After rTMS | Change in time of walking barefoot the distance of 10 meters with maximal speed, but safely, between baseline and directly after rTMS. | Posted | Mean | Standard Deviation | seconds | Before rTMS, directly (on the same day) after rTMS |
|
2 years.
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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 | Active rTMS | 10 hertz (Hz) rTMS will be administered over bilateral primary motor areas for the muscles of lower extremities. Therapy will include five daily sessions (on consecutive week days). In every sessions 3000 magnetic pulses of 90% of the resting motor threshold intensity will be elicited. rTMS: high frequency rTMS to induce the long term potentiation of primary motor areas for the muscles of lower extremities |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Seizure | Nervous system disorders | Non-systematic Assessment | In one patient a seizure occurred during the third session of real stimulation. It began with a tonic flexion of the hip and knee. Then, a loss of consciousness and generalized convulsions followed. The seizure resolved after three minutes. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Sleplessness | Nervous system disorders | Non-systematic Assessment | One female participant (62 years of age) complained about sleeplessness after the first two sessions of active stimulation. |
Limited number of sessions, which may decrease the magnitude of the therapeutic effect.
The abundant pharmacotherapy with baclofen could considerably reduce observed effects on spasticity.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Jakub Antczak | Jagiellonian University Medical College | +48 795 421 153 | jantczak@uj.edu.pl |
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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 | Jan 6, 2017 | Aug 24, 2021 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D015419 | Spastic Paraplegia, Hereditary |
| D000326 | Adrenoleukodystrophy |
| ID | Term |
|---|---|
| D015417 | Hereditary Sensory and Motor Neuropathy |
| D009421 | Nervous System Malformations |
| D009422 | Nervous System Diseases |
| D020271 | Heredodegenerative Disorders, Nervous System |
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16 patients with HSP or AMN will receive either active and sham stimulation in random order
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Sham stimulation will be provided by holding the stimulating coil perpendicularly to the scalp, which assures similar impression as during active stimulation but prevents significant magnetic field to reach the brain tissue.
Change in bilateral assessment of the strength of following movements: hip flexion, knee flexion and extension, ankle flexion and extension. Assessment will be made according to six degrees (0 to 5) MRC scale, with higher values representing stronger movements, which is better outcome. Values are averaged from all movements tested. |
| Baseline, directly (on the same day) after rTMS and 14 days later |
| Modified Ashworth Scale | Bilateral assessment of spasticity in following movements: hip flexion, knee flexion and extension, ankle flexion and extension. Assessment will be made according to six degrees (0 to 5) Modified Ashworth Scale, with higher values representing more severe spasticity, which is worse outcome. Values are averaged from all movements tested. | Baseline, directly (on the same day) after rTMS and 14 days later |
| Change From Baseline Walking Time in 10 Meter Walk Test to the Measurement Taken Two Weeks After rTMS | Change in time of walking barefoot the distance of 10 meters with maximal speed, but safely, between baseline and 14 days after finishing rTMS therapy. | Baseline, 14 days after rTMS |
| Antczak J, Pera J, Dabros M, Kozminski W, Czyzycki M, Wezyk K, Dwojak M, Banach M, Slowik A. The Effect of Repetitive Transcranial Magnetic Stimulation on Motor Symptoms in Hereditary Spastic Paraplegia. Neural Plast. 2019 May 12;2019:7638675. doi: 10.1155/2019/7638675. eCollection 2019. |
| BG001 | Sham rTMS, Then Active rTMS | First intervention: Sham stimulation will mimic the active one except that the stimulating coil will be held perpendicularly to the scalp, which assures similar impression as the active stimulation but prevents that significant magnetic field will reach brain tissue. The washout period will last at least one month. Second intervention: 10 hertz (Hz) rTMS will be administered over bilateral primary motor areas for the muscles of lower extremities. Therapy will include five daily sessions (on consecutive week days). In every sessions 3000 magnetic pulses of 90% of the resting motor threshold intensity will be elicited. rTMS: high frequency rTMS to induce the long term potentiation of primary motor areas for the muscles of lower extremities |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Central motor conduction time | Mean | Standard Deviation | milliseconds |
|
| Amplitude of motor evoked potentials | Mean | Standard Deviation | millivolts |
|
| Motor threshold for left abductor hallucis | Mean | Standard Deviation | percentage of the maximal stimulator out |
|
| Motor threshold for the right abductor hallucis | Mean | Standard Deviation | Percentage of the max stimulator output |
|
Sham stimulation will mimic the active one except that the stimulating coil will be held perpendicularly to the scalp, which assures similar impression as the active stimulation but prevents that significant magnetic field will reach brain tissue. rTMS: high frequency rTMS to induce the long term potentiation of primary motor areas for the muscles of lower extremities |
|
|
| Secondary | Change in Timed up and go Test | Time of standing up from a chair, walking three metres to cross a line drawn 3 meters ahead and going back to sit down on the chair. | Posted | Mean | Standard Deviation | seconds | Baseline, directly (on the same day) after rTMS and 14 days later |
|
|
|
| Secondary | Change in Medical Research Council Scale (MRC) | Change in bilateral assessment of the strength of following movements: hip flexion, knee flexion and extension, ankle flexion and extension. Assessment will be made according to six degrees (0 to 5) MRC scale, with higher values representing stronger movements, which is better outcome. Values are averaged from all movements tested. | Posted | Mean | Standard Deviation | score on a scale | Baseline, directly (on the same day) after rTMS and 14 days later |
|
|
|
| Secondary | Modified Ashworth Scale | Bilateral assessment of spasticity in following movements: hip flexion, knee flexion and extension, ankle flexion and extension. Assessment will be made according to six degrees (0 to 5) Modified Ashworth Scale, with higher values representing more severe spasticity, which is worse outcome. Values are averaged from all movements tested. | Posted | Mean | Standard Deviation | score on a scale | Baseline, directly (on the same day) after rTMS and 14 days later |
|
|
|
| Secondary | Change From Baseline Walking Time in 10 Meter Walk Test to the Measurement Taken Two Weeks After rTMS | Change in time of walking barefoot the distance of 10 meters with maximal speed, but safely, between baseline and 14 days after finishing rTMS therapy. | Posted | Mean | Standard Deviation | seconds | Baseline, 14 days after rTMS |
|
|
|
| 0 |
| 15 |
| 1 |
| 15 |
| 4 |
| 15 |
| EG001 | Sham rTMS | Sham stimulation will mimic the active one except that the stimulating coil will be held perpendicularly to the scalp, which assures similar impression as the active stimulation but prevents that significant magnetic field will reach brain tissue. rTMS: high frequency rTMS to induce the long term potentiation of primary motor areas for the muscles of lower extremities | 0 | 15 | 0 | 15 | 0 | 15 |
|
|
| Head ache | Nervous system disorders | Non-systematic Assessment | Mild head ache during first sessions of active rTMS |
|
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| D019636 | Neurodegenerative Diseases |
| D011115 | Polyneuropathies |
| D010523 | Peripheral Nervous System Diseases |
| D009468 | Neuromuscular Diseases |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D030342 | Genetic Diseases, Inborn |
| D020739 | Brain Diseases, Metabolic, Inborn |
| D001928 | Brain Diseases, Metabolic |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D020279 | Hereditary Central Nervous System Demyelinating Diseases |
| D056784 | Leukoencephalopathies |
| D003711 | Demyelinating Diseases |
| D038901 | X-Linked Intellectual Disability |
| D008607 | Intellectual Disability |
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
| D040181 | Genetic Diseases, X-Linked |
| D008661 | Metabolism, Inborn Errors |
| D018901 | Peroxisomal Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D000309 | Adrenal Insufficiency |
| D000307 | Adrenal Gland Diseases |
| D004700 | Endocrine System Diseases |