AMANTADINE AND TRANSCRANIAL MAGNETIC TRANSCRANIAL MAGNETIC STIMULATION FOR FATIGUE IN MULTIPLE SCLEROSIS: A PHASE III, CONTROLLED, RANDOMISED, DOUBLE-BLIND, CROSSOVER TRIAL

Prior treatment

• Patient diagnosed with a disease other than MS that may cause fatigue such as (but not limited to): a. Patient diagnosed with sleep apnoea treated with CPAP or not and who can justify fatigue apart from the disease. b. Patient with another associated autoimmune or rheumatological disease (lupus, rheumatoid arthritis...) that may justify the fatigue. In case of endocrine immune diseases, the patient is allowed to participate in the study if the analytical parameters are in range in the last 6 months and do not justify the fatigue. c. Patients with immune endocrine diseases. Inclusion is only allowed if the analytical parameters are in range in the last 6 months. d. Patients with diagnostic criteria for chronic fatigue syndrome. e. Patients with poorly controlled arterial hypertension or with decompensated, terminal or NYHA 3-4 heart failure. 2. Secondary epilepsy. 3. Present contraindications related to the treatments to be used (TMS or amantadine) such as: (a) Magnetically-sensitive metal on the head or within 12 inches (30.5 cm) of the TMS coil that cannot be removed. Objects that may contain such metal include: aneurysm clips or coils; carotid or cerebral stents; implanted stimulators; electrodes; ferromagnetic implants in the ears or eyes; bullets or shrapnel fragments; metal pellets, bullets or fragments; magnetically activated dental implants. b) History of epilepsy. c) Drugs that may lower the seizure threshold (antidepressants such as tricyclic antidepressants, antipsychotics, etc.). SSRIs are permitted at stable doses for the last 6 months. d) Hypersensitivity to amantadine. e) Severe heart disease, severe renal failure, angle-closure glaucoma. 4. Breast-feeding, pregnancy, or planning pregnancy in the next year. In case of fertile women, they must commit to the use of contraceptives throughout the study. In case of doubt at the time of inclusion, a pregnancy test will be performed. 5. Patients with a terminal medical illness with a life expectancy of less than one year. 6. Patient treated for malignant disease within the last three years. 7. Planning surgery during the trial period. 8. Any condition considered by the investigator team that may preclude participation/follow-up in the trial. 9. Alcohol or substance abuse within the past year. 10. Major psychiatric disorders (schizophrenia, schizoaffective disorders, bipolar, or obsessive-compulsive disorders, personality disorders). 11. Inability to communicate, poor command of the language or cognitive impairment that, in the opinion of the researcher, renders him/her incapable of carrying out the study. 12. Participation in another clinical trial with medication in the 4 months prior to inclusion. 13. Chronic use of drugs that may influence the results (unless they can be withdrawn prior to the start of the study): a. Antiepileptic drugs. Allowed in stable doses 3 months prior to inclusion. If it is necessary during the study because the patient has an epileptic seizure, it can be added. b. Diazepam and derivatives except in stable doses 3 months prior to inclusion. Modifications are permitted during the study. c. Baclofen, must be withdrawn with a period equal to or greater than 5 half-lives. d. SSRIs (Selective Serotonin Reuptake Inhibitors) except at stable doses 3 months prior to inclusion. If necessary during the study, may be added. e. Drugs that may lower the seizure threshold (antidepressants such as tricyclic antidepressants, antipsychotics, etc.). They are allowed in stable doses 3 months prior to inclusion. If necessary during the study, they can be added.

• Disability scale score (EDSS) at the time of recruitment (1, 5 to 4.5 points). 2. Fatigue Severity Scale (FSS) score greater than 4 points. 3. Beck Depression Inventory (BDI) score less than 30 points. 4. Not having presented an outbreak of the disease in at least three months prior to recruitment. recruitment. 5. Having undergone a four-week washout for any fatigue-related drugs related to fatigue: amantadine, modafinil, methylphenidate, acetyl-L-carnitine, cannabinol (delta-9-tetrahydrocannabinol, delta-9-tetrahydrocannabinol), cannabinol (delta-9-tetrahydrocannabinol and cannabidiol from Cannabis sativa L) and fampridine. fampridine. 6. Patient able to sign the Informed Consent form.