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Transcranial Magnetic Stimulation (TMS) in Multiple Sclerosis

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ClinicalTrials.gov Identifier: NCT04062331
Recruitment Status : Not yet recruiting
First Posted : August 20, 2019
Last Update Posted : August 21, 2019
Sponsor:
Collaborators:
Isaac Tunez-Fiñana
Eduardo Agüera-Morales
Information provided by (Responsible Party):
Javier Caballero-Villarraso, Maimónides Biomedical Research Institute of Córdoba

Brief Summary:

Background: Transcranial Magnetic Stimulation (TMS) is a technique based on the principles of electromagnetic induction. It applies pulses of magnetic radiation that penetrate the brain tissue, and it is a non-invasive, painless and practically innocuous procedure. Previous studies advocate the therapeutic capacity of TMS in several neurodegenerative and psychiatric processes, both in animal models and in human studies. Its uses in Parkinson's disease, Alzheimer's disease and in Huntington's chorea have shown improvement in the symptomatology and in the molecular profile, and even in the cellular density of the brain. Consequently, the extrapolation of these TMS results in the aforementioned neurodegenerative disease to other entities with etiopathogenic and clinical analogy would raise the relevance and feasibility of its use in multiple sclerosis (MS). The overall objective will be to demonstrate the effectiveness of the TMS in terms of safety and clinical improvement, as well as to observe the molecular changes in relation to the treatment.

Methods and design: Phase I clinical trial, unicentric, controlled, randomised, single blind. A total of 90 patients diagnosed with relapsing-remitting multiple sclerosis (RRMS) who meet all the inclusion criteria and do not present any of the exclusion criteria that are established and from which clinically evaluable results can be obtained. The patients included will be assigned under the 1:1:1 randomization formula, constituting three groups for the present study: 30 patients treated with natalizumab + white (placebo) + 30 patients treated with natalizumab + TMS (1 Hertz) + 30 patients treated with natalizumab + TMS (5 Hertz).

Discussion: Results of this study will inform on the efficiency of the TMS for the treatment of MS. The expected results are that TMS is a useful therapeutic resource to improve clinical status (main parameters) and neurochemical profile (surrogate parameters); both types of parameters will be checked.


Condition or disease Intervention/treatment Phase
Multiple Sclerosis Device: Transcranial Magnetic Stimulation (TMS) Drug: Placebos Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Phase I clinical trial, unicentric, controlled, randomised, single blind. Three arms.

The patients included will be assigned under the 1:1:1 randomization formula, constituting three groups for the present study: 30 patients treated with natalizumab + white (placebo) + 30 patients treated with natalizumab + TMS (1 Hertz) + 30 patients treated with natalizumab + TMS (5 Hertz).

Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Masking Description: Single-blind. Investigator who applies transcranial stimulation knows the kind of treatment (placebo, TMS 1 Hertz, TMS 5 Hertz). The patients don't know the frequency (measured Hertz) which TMS is running (0 Hertz= placebo, 1 Hertz, 5 Hertz) and the device and duration of sessions are the same.
Primary Purpose: Treatment
Official Title: Clinical and Neurochemical Effects of Transcranial Magnetic Stimulation (TMS) in Multiple Sclerosis
Estimated Study Start Date : October 1, 2019
Estimated Primary Completion Date : October 1, 2021
Estimated Study Completion Date : October 1, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Placebo Comparator: Placebo group
This group will be under standard therapy (natalizumab) plus Transcranial Magnetic Stimulation (TMS) without any frequency (device doesn't running; it means, device turned off) but the same duration of sessions.
Drug: Placebos
Administration of Transcranial Magnetic Stimulation at 0 Hz (the patient will be only under drug standar therapy)
Other Name: Sham group

Experimental: Group under TMS 1 Hertz treatment
1 Hertz group (1 Hertz ) will be under standard therapy (natalizumab) plus Transcranial Magnetic Stimulation (TMS) running with a frequency of 1 Hertz.
Device: Transcranial Magnetic Stimulation (TMS)

By means of the magnetic stimulator we induce a cerebral electric current that is able to obtain a motor potential in the first dorsal interosseous bone of the left hand.

The intervention procedure consists of two steps: First step: Obtaining the Motor Evoked Threshold at Rest: Each patient, regardless of to the group to which they belong will have his/her threshold evoked motor calculated at rest, by stimulation of the right motor cortex, evoking electromyographic responses in the contralateral muscles. Second step: Administration of TMS: To calculate the motive threshold as the percentage of the same to which the treatment will have to be applied, a device equipped with a coil. The treatment will be administered for 5 consecutive days, with 3 weeks of rest, between each stimulation. To complete a treatment period of 14 months. The stimulation with TMS will be carried out every day in the same time slot for 5 consecutive days every 4 weeks, during a period of 14 months.

Other Names:
  • Deep Brain Stimulation
  • Deep Transcranial Magnetic Stimulation

Experimental: Group under TMS 5 Hertz treatment
5 Hertz group (5 Hertz ) will be under standard therapy (natalizumab) plus Transcranial Magnetic Stimulation (TMS) running with a frequency of 5 Hertz .
Device: Transcranial Magnetic Stimulation (TMS)

By means of the magnetic stimulator we induce a cerebral electric current that is able to obtain a motor potential in the first dorsal interosseous bone of the left hand.

The intervention procedure consists of two steps: First step: Obtaining the Motor Evoked Threshold at Rest: Each patient, regardless of to the group to which they belong will have his/her threshold evoked motor calculated at rest, by stimulation of the right motor cortex, evoking electromyographic responses in the contralateral muscles. Second step: Administration of TMS: To calculate the motive threshold as the percentage of the same to which the treatment will have to be applied, a device equipped with a coil. The treatment will be administered for 5 consecutive days, with 3 weeks of rest, between each stimulation. To complete a treatment period of 14 months. The stimulation with TMS will be carried out every day in the same time slot for 5 consecutive days every 4 weeks, during a period of 14 months.

Other Names:
  • Deep Brain Stimulation
  • Deep Transcranial Magnetic Stimulation




Primary Outcome Measures :
  1. Clinical activity of the disease [ Time Frame: up 1 year ]
    Expanded Disability Status Scale. Score from 0 (total absence of disability) to 10 (death due to multiple sclerosis).

  2. Comprehensive clinical assessment of the disease [ Time Frame: up 1 year ]
    Multiple Sclerosis Functional Composite. It consists of three tests: Timed 25-Foot Walk, 9-Hole Peg Test and Paced Auditory Serial Addition Task. Score measured as a function of time. The higher, the worse the patient's condition.

  3. Cognitive function [ Time Frame: up 1 year ]
    Brief Repeatable Battery of Neuropsychological Test. It consists of the selective reminding test, the 10/36 spatial recall test, the symbol digit modalities test, the paced auditory serial addition test and the word list generation test. A higher score means a better status in a person.


Secondary Outcome Measures :
  1. Assessment of fatigue [ Time Frame: up 1 year ]
    Fatigue Impact Scale. It is based on items derived from interviews with MS patients concerning how fatigue impacts their lives. This instrument provides an assessment of the effects of fatigue in terms of physical, cognitive, and psychosocial functioning. It consists of 21 items. A higher score means a worse status in a person.

  2. Depression assessment [ Time Frame: up 1 year ]
    Beck depression scale It is a 21-question multiple-choice self-report inventory, one of the most widely used psychometric tests for measuring the severity of depression. Score from 0 to 63 (0 is no depression and 30-63 interval means several depression).

  3. Image analysis [ Time Frame: through study completion, an average of 1 year ]
    Nuclear Magnetic Resonance with and without contrast

  4. Lipoperoxidation molecules [ Time Frame: through study completion, an average of 1 year ]
    malondialdehyde (ng/mL) and 4-hydroxynonenal (ng/mL)

  5. Carbonylated proteins [ Time Frame: through study completion, an average of 1 year ]
    carbonyl reductase (nmol/mL) and carbonyl (nmol/mL)

  6. Complete blood count [ Time Frame: through study completion, an average of 1 year ]
    Complete blood count (with formula and count of red, white and platelet series)

  7. glucose [ Time Frame: through study completion, an average of 1 year ]
    glucose (mg/dL)

  8. Routine serum lipids [ Time Frame: through study completion, an average of 1 year ]
    cholesterol (mg/dL) and triglycerides (mg/dL)

  9. Routine serum proteins [ Time Frame: through study completion, an average of 1 year ]
    total proteins (g/L) and albumin (g/L)

  10. Transaminases [ Time Frame: through study completion, an average of 1 year ]
    aspartate aminotransferase (AST) (IU/L) and alanine aminotransferase (AST) (IU/L)

  11. creatine kinase (CK) [ Time Frame: through study completion, an average of 1 year ]
    CK (mg/mL)

  12. lactate dehydrogenase [ Time Frame: through study completion, an average of 1 year ]
    LDH (mg/mL)



Information from the National Library of Medicine

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Ages Eligible for Study:   14 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients diagnosed with RRMS in their inflammatory forms who have completed a 14-dose treatment with natalizumab.
  2. Normal analytical parameters, defined by: Leukocytes> 3000 / mcl, Neutrophils> 1500 / mcl, Platelets> 100000 / mcl, AST/ALT <2.5 IU / L, Creatinine <2.5 mg / dl.
  3. Patients of both sexes aged between 18 and 60 years.
  4. EDSS: between 3.0 and 6.5 points.
  5. Patients who give their informed consent for participation in the clinical trial.
  6. Women of childbearing potential must obtain negative results in a pregnancy test performed at the time of inclusion in the study and commit to using a medically approved method of contraception for the duration of the study.

Exclusion Criteria:

  1. Any active or chronic infection, including HIV infection, or hepatitis B or C.
  2. History of neoplasia (basal cell carcinoma of the skin and in situ carcinoma in remission are excluded for more than one year).
  3. Life expectancy severely limited by other co-morbidities.
  4. Endocrine disease such as diabetes, hyper or hypothyroidism.
  5. Chronic inflammatory or autoimmune disease such as ulcerative colitis, Crohn's disease, systemic lupus erythematosus and any other form of connective tissue disease or chronic arthropathy.
  6. Chronic obstructive pulmonary disease.
  7. Severe psychiatric illnesses.
  8. Hepatic, or renal, or cardiac dysfunction (including coronary heart disease and heart failure).
  9. Chronic anaemia.
  10. Pregnancy or risk of pregnancy (including refusal to use contraception).
  11. Women in breastfeeding period.
  12. Inability to undergo MRI scans.
  13. Inability to grant written informed consent.
  14. Taking lipid-lowering drugs and vitamin supplements.
  15. Treatment with steroids and/or non-steroidal anti-inflammatories, or alcohol intake 40 hours before the blood extraction and/or development of the different tests.
  16. Chronic alcoholism and/or abuse of drugs of abuse (sporadic or chronic).
  17. Metallic implants in the head.
  18. Cardiac pacemaker device.
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Javier Caballero-Villarraso, Professor, Maimónides Biomedical Research Institute of Córdoba
ClinicalTrials.gov Identifier: NCT04062331    
Other Study ID Numbers: EMTr-EMRR, ver - 3, 21/11/2017
First Posted: August 20, 2019    Key Record Dates
Last Update Posted: August 21, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: To publish the protocol study and its results in Scientific Journals
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: The protocol study may be published in the last quarter of 2019. The results could be published at the end of the study (about 2022).
Access Criteria: Throug the website of research group https://www.imibic.org/grupo/35 or after request it (by previous e-mail from one of investigators)

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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
Keywords provided by Javier Caballero-Villarraso, Maimónides Biomedical Research Institute of Córdoba:
clinical trial
multiple sclerosis
neurodegenerative diseases
transcranial magnetic stimulation
deep brain stimulation
neurochemistry
Additional relevant MeSH terms:
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Multiple Sclerosis
Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases