Evaluation of Amantadine Hydrochloride and Transcranial Magnetic Stimulation for Fatigue Management in Multiple Sclerosis: A Phase III Randomized Controlled Trial

Trial ID: 2024-516732-97-00
Protocol: FETEM
Sponsor: Fundacion Para La Investigacion Biomedica Del Hospital Clinico San Carlos

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Diseases & Conditions

Multiple sclerosis

Objectives

The primary objective of this study is to compare the effect of **transcranial magnetic stimulation (TMS)** and **amantadine** alone or in combination therapy with placebo for the treatment of fatigue in patients with **multiple sclerosis (MS)**. The evaluation will be conducted using the Modified Fatigue Impact Scale (MFIS) at 6 weeks. This objective is clinically relevant as fatigue is a common and debilitating symptom in MS, significantly impacting patients' quality of life and daily functioning.

Secondary objectives include assessing changes in cognition, depression, and quality of life using validated reference scales. Additionally, a safety and cost-effectiveness analysis will be performed. These secondary objectives aim to provide a comprehensive understanding of the therapeutic impact and feasibility of the interventions beyond fatigue management.

Participants

The clinical trial focuses on individuals diagnosed with **multiple sclerosis (MS)**, aiming to evaluate the effects of TMS and amantadine, alone or in combination, on fatigue as measured by the MFIS scale. The study population includes both male and female participants, with an age range spanning from 18 to 64 years. Participants are generally in good health, with specific criteria ensuring the absence of recent disease outbreaks and a requirement for a washout period from certain fatigue-related medications. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants in the study.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, controlled, crossover study to evaluate the efficacy of **amantadine hydrochloride** and transcranial magnetic stimulation (TMS) in treating fatigue associated with **multiple sclerosis (MS)**. The trial aims to compare the effects of TMS and amantadine, both individually and in combination, against a placebo over a period of six weeks, as measured by the Modified Fatigue Impact Scale (MFIS). The study is categorized as a low-intervention trial and is expected to conclude by November 2024, with recruitment having commenced in November 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as a Disability Scale Score (EDSS) between 1.5 and 4.5, a Fatigue Severity Scale (FSS) score greater than 4, and a Beck Depression Inventory (BDI) score of less than 30. Additionally, participants must not have experienced a disease outbreak in the three months prior to recruitment and must have completed a four-week washout period for any fatigue-related medications. Following the screening, participants will be randomized into different treatment arms and will attend follow-up visits at the beginning and end of each treatment phase to evaluate primary and secondary endpoints, including changes in MFIS scores, quality of life assessments, and depressive symptomatology.

The expected duration of participant involvement is approximately six weeks, aligning with the maximum treatment period. Conditions that may lead to early termination from the study include non-compliance with the study protocol, withdrawal of consent, or the occurrence of adverse events that compromise participant safety. The end-of-study visit will involve a comprehensive assessment of all study endpoints and the collection of final data to determine the overall effectiveness of the interventions. Throughout the trial, the use of **amantadine hydrochloride** will be administered orally in the form of hard capsules, with a maximum daily dose of 200 mg and a total dose not exceeding 7700 mg over the study period.

Treatment

The clinical trial involves the administration of **Amantadine Hydrochloride**, marketed under the name "Amantadine Level 100 mg cápsulas duras." This experimental medication is provided in the form of hard capsules, each containing 100 mg of the active substance. The route of administration is **oral**, with a maximum daily dose of 200 mg. The total maximum dose over the treatment period is 7700 mg. The treatment duration is set for a maximum of 6 weeks. Amantadine Hydrochloride is a dopaminergic agent that can also act as an antiviral and antiparkinsonian. The medication is manufactured by Laboratorios ERN, S.A., and is not a pediatric formulation.

In addition to the experimental medication, the trial utilizes a medical device known as the MAGSTIM®RAPID2. This device is a magnetic nerve stimulator system intended for the stimulation of peripheral nerves and the human cortex for diagnostic and research purposes. It is used off-label in this study. The device is equipped with components such as a Unit Power Status Indicator, ON/OFF/STANDBY switch, ARMED Indicator, Coil OUTPUT Socket, PSU Power Status Indicator, and ARMED/FAULT Indicator. The device has a CE mark reference of CE10982, certified by BSI Group The Netherlands.

The trial is designed to compare the effects of Transcranial Magnetic Stimulation (TMS) and Amantadine, alone or in combination, against a placebo for the treatment of fatigue in patients with **Multiple Sclerosis** (MS). The primary outcome measure is the change in fatigue levels as determined by the Modified Fatigue Impact Scale (MFIS) over a 6-week period. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment protocol.

Efficacy

Efficacy in this clinical trial will be assessed primarily through the change in values of the **Modified Fatigue Impact Scale (MFIS)** questionnaire, which serves as the main study variable for evaluating effectiveness. The MFIS is a validated tool used to measure the impact of fatigue on patients with Multiple Sclerosis (MS). The primary endpoint will be the comparison of the effect of transcranial magnetic stimulation (TMS) and amantadine, alone or in combination, against a placebo for the treatment of fatigue in MS, as determined by the MFIS scale at 6 weeks.

Secondary endpoints include the assessment of patient-perceived quality of life using the SF-12 scale, with changes in mean scores evaluated between the time of inclusion and at the beginning and end of each phase. Additionally, the **Beck Depression Inventory-II** will be utilized to assess depressive symptomatology at inclusion, and at the beginning and end of each phase. Total costs per patient, including hospitalization and treatment costs, as well as other healthcare expenses, will also be measured. These assessments will provide a comprehensive evaluation of the treatment's impact on both clinical and economic outcomes.

Inclusion and Exclusion Criteria

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Inclusion Criteria

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.

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Exclusion Criteria

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.