Treatment of Fatigue With Methylphenidate, Modafinil and Amantadine in Multiple Sclerosis

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