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

December 4, 2023 updated by: Jorge Matías-Guiu, Hospital San Carlos, Madrid

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

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Estimated)

144

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Spain
      • Cadiz, Spain, 11009
      • Madrid, Spain, 28040
        • Recruiting
        • Hospital Clinico San Carlos
        • Contact:
        • Principal Investigator:
          • Jorge Matias-Guiu Guia, MD PhD
        • Sub-Investigator:
          • Jordi Matias-Guiu Antem, MD PhD
      • Madrid, Spain, 28007
        • Recruiting
        • Hospital General Gregorio Maranon
        • Contact:
      • Santa Cruz De Tenerife, Spain, 38010
        • Recruiting
        • Hospitalario Universitario Nuestra Señora de la Candelaria
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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
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.
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
To assess the fatigue severity
Time Frame: 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).
6 weeks after starting treatment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
To assess the cognitive condition
Time Frame: 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).
6 weeks after starting treatment
To assess the depression condition
Time Frame: 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).
6 weeks after starting treatment
To assess the quality of life
Time Frame: 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).
6 weeks after starting treatment
Safety assessment
Time Frame: 6 months after randomization
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
Time Frame: 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.
6 weeks after starting treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Hospital San Carlos, Madrid

Investigators

  • Principal Investigator: Jorge Matias-Guiu Guia, MD PhD, Hospital San Carlos, Madrid

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 28, 2022

Primary Completion (Estimated)

July 15, 2024

Study Completion (Estimated)

February 28, 2025

Study Registration Dates

First Submitted

March 20, 2023

First Submitted That Met QC Criteria

April 9, 2023

First Posted (Actual)

April 12, 2023

Study Record Updates

Last Update Posted (Estimated)

December 11, 2023

Last Update Submitted That Met QC Criteria

December 4, 2023

Last Verified

December 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • FETEM

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

The data used will be deposited in a suitable repository that will be complied with the requirements of ISCIII and any other applicable national regulations. Due to the data collected retain their personal character and they can be traced back, they will be safeguarded maintaining their integrity and confidentiality. These data cannot be openly shared after the project's completion. The licenses and access permissions will be determined based on the following criteria before the project's completion: a) The guidelines or recommendations of ISCIII. b) The policies established by the data repository to which the data will be sent. c) Possible restrictions on data publication that may arise from applicable protection schemes for the project's results. In any case, the requirements set forth by ISCIII in the funding call received will be complied with, as well as those considered in other applicable regulations. The dataset used will be stored in a locked condition for a period of 5 years.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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