Amantadine and Transcranial Magnetic Stimulation for Treating Fatigue in Multiple Sclerosis

Study Overview
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Brief Summary
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Multiple Sclerosis (MS) is the most frequent cause of non-traumatic disability in people under 55 years of age. Fatigue is the most frequent and disabling symptom in the disease, and for which there is no effective treatment. Among the proposed drugs, amantadine is the one that could be most useful, although up to now it has not been adequately demonstrated due to a lack of sufficiently powerful and methodologically appropriate clinical trials. Transcranial magnetic stimulation (TMS) has recently been proposed as a useful treatment for fatigue in MS in preliminary studies.

Detailed Description
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Multiple Sclerosis (MS) is the most frequent cause of non-traumatic disability in people under 55 years of age. Fatigue is the most frequent and disabling symptom in the disease, and for which there is no effective treatment. Among the proposed drugs, amantadine is the one that could be most useful, although up to now it has not been adequately demonstrated due to a lack of sufficiently powerful and methodologically appropriate clinical trials. Transcranial magnetic stimulation (TMS) has recently been proposed as a useful treatment for fatigue in MS in preliminary studies. The main objective of the study is to evaluate the change in the severity of fatigue in MS patients undergoing treatment with amantadine, TMS and both in combination, compared to placebo. A randomized, placebo-controlled, crossover, double-blind clinical trial will be conducted. As secondary objectives, changes in cognition, depression and quality of life will be evaluated. For all this, the reference scales adequately validated for each of the objectives will be used.

Official Title
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Amantadine and Transcranial Magnetic Stimulation for Treating Fatigue in Multiple Sclerosis: Phase III Study, Controlled, Randomized, Crossed Over and Double Blind.

Conditions
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Multiple Sclerosis, Fatigue

Intervention / Treatment
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* Device: Transcranial Magnetic Stimulation
* Drug: Amantadine Hydrochloride 100 mg (milligrams) Oral Capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Expanded Disability Status Scale mark 1.5 - 4.5 Fatigue Severity Scale > 4 Beck Depression Inventory < 30 No relapse for, at least, three month prior to screening Drug washout period = 4 weeks for any fatigue aimed drug Patient capable to sign the informed consent Exclusion Criteria: Fatigue causing disease other than multiple sclerosis: sleep apnea other autoimmune disease that could be explain the fatigue. endocrine autoimmune disease if the blood test is not in range in the last 6 month. patient with diagnosis of chronic fatigue Patient with high blood pressure out of range or decompensated heart failure or New York Heart Association (NYHA) 3-4. Secondary Epilepsy or neuropathic chronic pain which requires continuous treatment. Contraindication for trial treatment: Some kind of magnetic metal. Epilepsy antecedents. Any drugs that could decrease the seizure threshold Amantadine sensitivity Cardiopathy disease, severe kidney failure, Angle-closure glaucoma Breastfeeding, pregnancy, or pregnancy planning phase in the next year. Of childbearing potential and willing to use an acceptable method of contraception during the study period. Patient with a terminal disease with no more than one year life expectancy. Patient has been treated for a maligned disease in the past three years. A scheduled surgery in the course of the trials. Any condition that a member of research team consider could affect to participation/follow up patient. Alcoholic o toxics condition in the last year. Major mental disorders Poor communication skills or poor cognitive condition. Other trial participation in the previous 4 month. Use a chronic drug that could interfere in the clinical outcome.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: All patients will receive all possible combinations (TMS+placebo, TMS+amantadine, TMS sham+amantadine, TMS sham+placebo), the only difference being the sequence in which they are administered.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Amantadine<br> | Drug: Amantadine Hydrochloride 100 mg (milligrams) Oral Capsule<br>* It will be used at a dose of 100 mg, 1 capsule a day for 1 week, followed by 2 daily doses of 100 mg until completing 6 weeks in total. After completing the treatment phase, the dose will be de-escalated (1 capsule a day for 5 days and discontinued). In the case of placebo amantadine capsules, they will have the same organoleptic characteristics as amantadine. The start, maintenance and de-escalation pattern will be identical.<br>|
| Placebo Comparator: Placebo<br> | Drug: Amantadine Hydrochloride 100 mg (milligrams) Oral Capsule<br>* It will be used at a dose of 100 mg, 1 capsule a day for 1 week, followed by 2 daily doses of 100 mg until completing 6 weeks in total. After completing the treatment phase, the dose will be de-escalated (1 capsule a day for 5 days and discontinued). In the case of placebo amantadine capsules, they will have the same organoleptic characteristics as amantadine. The start, maintenance and de-escalation pattern will be identical.<br>|
| Experimental: TMS<br> | Device: Transcranial Magnetic Stimulation<br>* TMS is a technique for electrical stimulation of brain tissue by generating a magnetic field, which modulates neural activity at the stimulation site and in interconnected neural networks. The treatment will be applied to the left dorsolateral prefrontal region. Each patient will receive 3 sessions per week of approximately 10 minutes for 6 weeks. In the case of TMS sham, a placebo coil will be used, which is indistinguishable from the therapeutic one. In addition, the sessions will be carried out with the same frequency, so the patient will be unaware of the treatment they are receiving.<br>* Other names: TMS;|
| Sham Comparator: TMS sham<br> | Device: Transcranial Magnetic Stimulation<br>* TMS is a technique for electrical stimulation of brain tissue by generating a magnetic field, which modulates neural activity at the stimulation site and in interconnected neural networks. The treatment will be applied to the left dorsolateral prefrontal region. Each patient will receive 3 sessions per week of approximately 10 minutes for 6 weeks. In the case of TMS sham, a placebo coil will be used, which is indistinguishable from the therapeutic one. In addition, the sessions will be carried out with the same frequency, so the patient will be unaware of the treatment they are receiving.<br>* Other names: TMS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the fatigue severity | To compare the effect of TMS and amantadine alone or in combination therapy compared with placebo on fatigue determined using the Modified Fatigue Impact Scale (Total MFIS score: Range from 0 to 84, from minimal to severe fatigue). | 6 weeks after starting treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the cognitive condition | To compare the effect of TMS and amantadine alone or in combination therapy compared to placebo on cognition determined by the Symbol Digit Modalities Test (SDMT). | 6 weeks after starting treatment | 
| To assess the depression condition | To compare the effect of TMS and amantadine alone or in combination therapy compared to placebo on depression measured using the Beck Depression Inventory Scale (BDI-II score: Range from 0 to 63, from minimal to severe depression). | 6 weeks after starting treatment | 
| To assess the quality of life | To compare the effect of TMS and amantadine alone or in combination therapy compared to placebo on the quality of life determined by the Short Form 12 Mental Health scale (SF-12 score: Range from 0 to 100, from worse to better physical and mental health functioning). | 6 weeks after starting treatment | 
| Safety assessment | Analyze the incidence of the adverse events detected in each of the branches, whether or not with multiple sclerosis | 6 months after randomization | 
| Cost-effectivity assessment | Determine the cost-effectiveness of the different interventions. The total costs of hospitalization and treatment, as well as other health care, will be measured. | 6 weeks after starting treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Amantadine, Multiple Sclerosis, Fatigue, Transcranial Magnetic Stimulation (TMS), Modified Fatigue Impact Scale (MFIS)