TRIUMPHANT-MS

Treatment tested

• Amantadine
• Modafinil

  Dopamine transporter inhibitor

• Methylphenidate

  Dopamine transporter inhibitor|Norepinephrine transporter inhibitor

Placebo or sham

• Placebos

Other measures (2)

Inclusion criteria: * Age 18 years and older. * Females of childbearing age must have a negative urine pregnancy test at baseline and use an effective method of contraception during the study. * Diagnosis of MS (according to the 2010 McDonald criteria). * Expanded Disability Status Scale (EDSS) score at the time of screening 0.0-7.0. * Fatigue reportedly present and screening Modified Fatigue Impact Scale (MFIS) score more than 33. * At least a two-week washout for any fatigue-related drug, including study medications. Exclusion criteria: * Neurodegenerative disorders other than relapsing or progressive MS. * Breastfeeding or pregnant. * History of coronary artery disease or congestive heart failure. * Uncontrolled hypertension at screening (history of high blood pressure and screening systolic blood pressure >160 or diastolic blood pressure>100). * Glomerular Filtration Rate (GFR) (glomerular filtration rate) \< 50. * Abnormal liver function at screening (AST or Alanine Aminotransferase (ALT) more than twice the upper limit of normal). * Terminal medical conditions. * Currently treated for active malignancy. * Planned surgery or move within 8 months of screening. * Alcohol or substance abuse in the past year (except marijuana or other cannabinoids). * A history of intolerance or allergic or anaphylactic reaction to amantadine, modafinil, methylphenidate or any component of the preparation. * Clinically unstable medical or psychiatric disorders that require acute treatment as determined by the PI. * Concurrent use of monoamine oxidase inhibitors-B. * Hypersensitivity/idiosyncrasy to sympathomimetic amines * Inability to communicate or answer the questionnaires in English or Spanish. * Severe untreated anemia (blood hemoglobin \<9gr/dl) * History of untreated hypothyroidism * History of untreated sleep apnea * History of long QT syndrome, atrial fibrillation or tachyarrhythmias (other than sinus tachycardia) * History of ischemic or hemorrhagic stroke * History of glaucoma * History of Tourette syndrome

Randomized, placebo-controlled, crossover, 4-sequence, 4-period, double-blind (participants and investigators), multicenter trial of 3 commonly used medications for treatment of MS-related fatigue (amantadine, modafinil, methylphenidate) versus placebo in fatigued subjects with MS defined by McDonald Criteria.