Methylphenidate as Treatment Option of Fatigue in Multiple Sclerosis

Study Overview
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Brief Summary
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Fatigue is a common symptom in multiple sclerosis (MS) that is characterized by physical and/or mental exhaustion. Fatigue is difficult to treat and treatment efficacy of available therapy is limited. The goal of this study is to determine whether MS-associated fatigue improves after 6 weeks of methylphenidate therapy. Treatment efficacy will be measured by a questionnaire called Fatigue Severity Scale (FSS).

Detailed Description
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The management oft fatigue comprises nonpharmacologic approaches like exercise, cooling procedures, nutrition, and energy conservation programmes. These strategies should be considered as first-line options since they add to overall wellbeing, have no side effects and increase the patient's autonomy. However, in most cases these strategies will not suffice to keep the patient symptom free on the long term. Also, patients with overwhelming and severe fatigue will be unlikely to engage in exercise. In these cases adding pharmacologic therapy will be the next step. Until now, Amantadine, Modafinil, and Pemoline have been used among others, with some success. Also antidepressants like buprione, fluoxetine, and venlafaxine have been used although they have never been systematically studied for the management of MS-related fatigue. However, if a mood disorder is present, it is appropriate to treat it before pursuing pharmacologic therapy of fatigue. Nevertheless, the response rate of all pharmacologic therapies of MS-related fatigue is not totally convincing making alternative pharmacologic therapies furthermore desirable. Methylphenidate is an antagonist of dopamine and norepinephrine transporters on the presynaptic neuronal cell membrane. Reduced reuptake results in an increase in extracellular levels of both neurotransmitters. Until now, methylphenidate has been successfully used to treat fatigue in HIV and parkinson´s disease, data on its efficacy in MS are not available. The aim of this study is to determine the efficacy of methylphenidate treatment in MS-associated fatigue. The treatment phase will be 6 weeks and treatment efficacy will be measured by validated questionnaires (Fatigue Severity Scale FSS, modified Fatigue Impact Scale MFIS) and by a neuropsychological test (Test for Attentional Performance).

Official Title
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Methylphenidate Modified-release as Treatment of MS-associated Fatigue. A Single-center Randomized Double-blind Placebo-controlled Study.

Conditions
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Multiple Sclerosis, Fatigue

Intervention / Treatment
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* Drug: Methylphenidate modified release
* Drug: Maltodextrin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of multiple sclerosis according to McDonalds criteria. Age > 18 years Fatigue as measured by Fatigue Severity Scale Signed informed consent Exclusion Criteria: Known allergy or hypersensitivity to Methylphenidate or any of its ingredients Marked anxiety, tension and agitation Patients with glaucoma or hyperthyroidism Patients with motor-tics, a family history or diagnosis of Tourette´s syndrome Treatment with monoamine oxidase inhibitors, also within a minimum of 14 days following discontinuation (hypertensive crisis may result). Phaeochromocytoma Pre-existing cardiovascular disorders including severe hypertension, angina, arterial occlusive disorder, heart failure, haemodynamically significant congenital heart disease, cardiomyopathies, myocardial infarction, potentially life-threatening arrhythmias and channelopathies. History of drug dependence or alcoholism History of seizures Pregnant women or females of childbearing potential who want to become pregnant within the study period. Severe psychiatric disorders Change of any medication treatment <8 weeks before starting the study Participation in any other clinical trial at the same time

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Methylphenidate modified release<br>The active agents is racemic methylphenidate hydrochloride, modified release, a mild central nervous system stimulant (pharmacotherapeutic group: psychostimulants). Study medication will be taken once daily. Initially patients will be provided with 20mg and 30mg capsules of study medication. They are instructed to take 20mg within the first week and within the second week 30mg capsules. Visit 2 is scheduled two weeks after baseline and at Visit 2 patients will be provided with 40mg capsules and instructed to take them for the rest of the study. | Drug: Methylphenidate modified release<br>* Ritalin 20mg once daily within the first week, Ritalin 30mg once daily within the second week and afterwards Ritalin 40mg will be taken once daily throughout the remaining active treatment phase.<br>* Other names: Ritalin LA 40mg;|
| Placebo Comparator: Maltodextrin<br>Study medication has to be taken once daily. Initially patients will be provided with 20mg and 30mg capsules of study medication. They are instructed to take 20mg within the first week and within the second week 30mg capsules. Visit 2 is scheduled two weeks after baseline and at Visit 2 patients will be provided with 40mg capsules and instructed to take them for the rest of the study. | Drug: Maltodextrin<br>* Study medication will be taken once daily. Patients will take 20mg of study medication within the first week, 30mg within the second week and afterwards 40mg of study medication throughout the remaining active study period.<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of Fatigue as measured by Fatigue Severity Scale | The Fatigue severity scale is one of the most commonly used self questionnaires to measure fatigue. The FSS questionnaire contains nine statements that rate the severity of fatigue symptoms. A low value (e.g., 1); indicates strong disagreement with the statement, whereas a high value (e.g., 7); indicates strong agreement. A total score of 36 or more suggests presence of fatigue. | Baseline versus follow-up at 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of Fatigue as measured by Modified Fatigue Impact Scale (MFIS) | This instrument provides an assessment of the effects of fatigue in terms of physical, cognitive, and psychosocial functioning. The full-length MFIS consists of 21 items. The MFIS is a structured, self-report questionnaire that the patient can generally complete with little or no intervention from an interviewer. The total score for the MFIS is the sum of the scores for the 21 items. Individual subscale scores for physical, cognitive, and psychosocial functioning can also be generated by calculating the sum of specific sets of items. All items are scaled so that higher scores indicate a greater impact of fatigue on a patient's activities | Baseline versus follow up at 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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multiple sclerosis, fatigue, fatigue severity scale, fatigue impact scale, quality of life