FETEM: Amantadine and Transcranial Magnetic Stimulation for Treating Fatigue in Multiple Sclerosis

Sponsor

Hospital San Carlos, Madrid (Other)

Overall Status

Recruiting

CT.gov ID

NCT05809414

Collaborator

(none)

144

Enrollment

Locations

Arms

Anticipated Duration (Months)

Patients Per Site

1.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis Fatigue	Device: Transcranial Magnetic Stimulation Drug: Amantadine Hydrochloride 100 mg (milligrams) Oral Capsule	Phase 3

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

144 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

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.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 (Participant, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Nov 28, 2022

Anticipated Primary Completion Date :

Jul 15, 2024

Anticipated Study Completion Date :

Feb 28, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Amantadine	Drug: Amantadine 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.
Placebo Comparator: Placebo	Drug: Amantadine 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.
Experimental: TMS	Device: Transcranial 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. Other Names: TMS
Sham Comparator: TMS sham	Device: Transcranial 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. Other Names: TMS

Outcome Measures

Primary Outcome Measures

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 Outcome Measures

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).
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).
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
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Hospital Puerta del Mar	Cadiz	Spain	11009
2	Hospital General Gregorio Marañon	Madrid	Spain	28007
3	Hospital Clínico San Carlos	Madrid	Spain	28040
4	Hospitalario Universitario Nuestra Señora de la Candelaria	Santa Cruz De Tenerife	Spain	38010