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.

This is a 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.

Using a balanced Latin-square crossover design, subjects will be allocated, in a double-blind, randomized fashion, to one of the four treatment sequences (Figure 1): 1) amantadine, placebo, modafinil, methylphenidate; 2) placebo, methylphenidate, amantadine, modafinil; 3) modafinil, amantadine, methylphenidate, placebo; and 4) methylphenidate, modafinil, placebo and amantadine. Each medication will be titrated over four weeks to the participants' highest tolerated dose or the pre-defined highest dose. The dosing and titration schedule of the study medications are depicted in Figure 2. Each treatment period will be 6 weeks and there will be a 2-week washout period between each treatment period. At the beginning of the trial, a biostatistician at University of California, San Francisco (UCSF) will prepare a concealed allocation schedule, randomly assigning the four sequences, in blocks of 4, to a consecutive series of numbers and at the time of enrollment, each participant will be assigned the next consecutive number (and hence the sequence of study medications).

The primary endpoint of the study will be fatigue severity as measured by the MFIS score, between 26th and 35th day of each treatment period (while the patient is taking the maximal tolerated or target dose). The MFIS is a validated patient-reported outcome. The questionnaire will be administered remotely (through internet, phone or mailed forms) and the participants can answer the questions in few minutes while at home or at their work place. The questionnaire has been validated in English and Spanish.

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

Adverse events were collected during each six-week medication period.

The numbers in the adverse event section are patients who constitute the safety dataset. These are patients who at least took one dose of that medication (whether or not they had their efficacy measured).

Double-blind