Fatigue, Multiple Sclerosis
Conditions
Keywords
Amantadine, Multiple Sclerosis, Fatigue, Transcranial Magnetic Stimulation (TMS), Modified Fatigue Impact Scale (MFIS)
Brief summary
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
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.
Interventions
DEVICETranscranial Magnetic Stimulation
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.
DRUGAmantadine Hydrochloride 100 mg (milligrams) Oral Capsule
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.
Sponsors
Hospital San Carlos, Madrid
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Expanded Disability Status Scale mark 1.5 - 4.5 2. Fatigue Severity Scale \> 4 3. Beck Depression Inventory \< 30 4. No relapse for, at least, three month prior to screening 5. Drug washout period = 4 weeks for any fatigue aimed drug 6. Patient capable to sign the informed consent
Exclusion criteria
1. Fatigue causing disease other than multiple sclerosis: 1. sleep apnea 2. other autoimmune disease that could be explain the fatigue. 3. endocrine autoimmune disease if the blood test is not in range in the last 6 month. 4. patient with diagnosis of chronic fatigue 5. Patient with high blood pressure out of range or decompensated heart failure or New York Heart Association (NYHA) 3-4. 2. Secondary Epilepsy or neuropathic chronic pain which requires continuous treatment. 3. Contraindication for trial treatment: 1. Some kind of magnetic metal. 2. Epilepsy antecedents. 3. Any drugs that could decrease the seizure threshold 4. Amantadine sensitivity 5. Cardiopathy disease, severe kidney failure, Angle-closure glaucoma 4. 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. 5. Patient with a terminal disease with no more than one year life expectancy. 6. Patient has been treated for a maligned disease in the past three years. 7. A scheduled surgery in the course of the trials. 8. Any condition that a member of research team consider could affect to participation/follow up patient. 9. Alcoholic o toxics condition in the last year. 10. Major mental disorders 11. Poor communication skills or poor cognitive condition. 12. Other trial participation in the previous 4 month. 13. Use a chronic drug that could interfere in the clinical outcome.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To assess the fatigue severity | 6 weeks after starting treatment | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety assessment | 6 months after randomization | Analyze the incidence of the adverse events detected in each of the branches, whether or not with multiple sclerosis |
| To assess the quality of life | 6 weeks after starting treatment | 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). |
| To assess the cognitive condition | 6 weeks after starting treatment | 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). |
| To assess the depression condition | 6 weeks after starting treatment | 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). |
| Cost-effectivity assessment | 6 weeks after starting treatment | Determine the cost-effectiveness of the different interventions. The total costs of hospitalization and treatment, as well as other health care, will be measured. |
Countries
Spain
Contacts
Primary ContactJorge Matias-Guiu Guia, MD PhD
Backup ContactJordi Matias-Guiu Antem, MD PhD
Outcome results
None listed