Amantadine and Transcranial Magnetic Stimulation for Treating Fatigue in Multiple Sclerosis

Phase 3

Recruiting

• Conditions: Multiple Sclerosis; Fatigue
• Interventions: Drug: Amantadine Hydrochloride 100 mg (milligrams) Oral Capsule; Device: Transcranial Magnetic Stimulation

• Registration Number: NCT05809414
• Lead Sponsor: Hospital San Carlos, Madrid

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.

Study Timeline

• Study Start: 2022-11-28
• Study First Submitted: 2023-03-20
• Study First Submitted QC: 2023-04-09
• Study First Posted: 2023-04-12
• Status Verified: 2023-12
• Last Update Submitted: 2023-12-04
• Last Update Posted: 2023-12-11
• Primary Completion: 2024-07-15
• Study Completion: 2025-02-28

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 144

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Amantadine	Amantadine Hydrochloride 100 mg (milligrams) Oral Capsule	-
Placebo	Amantadine Hydrochloride 100 mg (milligrams) Oral Capsule	-
TMS	Transcranial Magnetic Stimulation	-
TMS sham	Transcranial Magnetic Stimulation	-

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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.
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).
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).

Trial Locations

Locations (4)

Hospital General Gregorio Marañon; 🇪🇸 Madrid, Spain

Hospital Clínico San Carlos; 🇪🇸 Madrid, Spain

Hospital Puerta del Mar; 🇪🇸 Cadiz, Spain

Hospitalario Universitario Nuestra Señora de la Candelaria; 🇪🇸 Santa Cruz De Tenerife, Spain