A Study of Oxidative Pathways in MS Fatigue
Condition: Progressive Multiple Sclerosis; Fatigue
MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Sclerosis; Fatigue
Intervention: N-acetyl cysteine; Placebo
Intervention description: 1250 mg of N- acetyl cysteine taken three times daily; placebo taken three times daily
Intervention MeSH terms: Acetylcysteine; N-monoacetylcystine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 15.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No

Summary:

      This is a 4-week randomized, placebo-controlled, parallel group, double-blind, single center
      trial on effect of N-acetyl cysteine versus placebo on fatigue in patients with progressive
      MS defined by McDonald criteria. Subjects who enter the treatment phase of study, will be
      randomly assigned to either N-acetyl cysteine (1250 mg three times a day) or placebo (three
      times a day) for 4 weeks. There will be 3 in-person study visits (screening, baseline, and
      week 4) and 2 visits over the phone (week 2, and week 6 which is 2 weeks after completing
      last study drug dose). Visits will all occur in the morning to maximize consistency of
      assessments and evaluate main outcomes within 2 hours of morning dose of study medication.
      Fatigue questionnaires, and research samples will be obtained before neurological
      examination, or magnetic resonance imaging. Research blood draws will be obtained just after
      fatigue questionnaire completion. Brain spectroscopy will be obtained less than 2 hours after
      morning dose of study drug to maximize detection of the biological effect of study
      medication.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Age 18 through 75 years included.

          2. Ability to sign the informed consent before participation.

          3. Females of childbearing age must have a negative pregnancy test at screening and use
             an effective method of contraception during the study participation period.

          4. Diagnosis of primary or secondary progressive multiple sclerosis (according to the
             2010 McDonald criteria).

          5. Time since first reported MS symptoms more than one year.

          6. EDSS score at the time of screening 2.0-6.5.

          7. Fatigue reportedly present and screening MFIS more than 38 for patients who will be
             enrolled in the randomized placebo controlled part of the study. MFIS score of less
             than 38 is required for patients who are controls on the study.

        Exclusion Criteria:

          1. History of MS relapses in the previous 3 months.

          2. Neurodegenerative progressive neurological disorders other than progressive MS.

          3. Breastfeeding

          4. History of bleeding disorders

          5. Abnormal results of liver function test at screening (AST or ALT more than twice the
             upper limit of normal).

          6. Receiving or about to start interferon beta or immunosuppressive medications (e.g.
             cyclophosphamide, mitoxantrone, methotrexate, mycophenolate mofetil) as these
             medication can be associated with fatigue.

          7. Starting or changing the dose of other MS disease-modifying medications (including
             monoclonal antibodies such as rituximab, ocrelizumab, alemtuzumab, daclizumab) within
             3 months of baseline visit.

          8. No ongoing steroid treatment and no steroid treatment in the prior month.

          9. Inability to undergo MRI scans (e.g. weight>350 pounds, severe claustrophobia, metal
             in the body).

         10. Medical terminal conditions.

         11. Currently treated for active malignancy or metastatic malignancy that has been treated
             in the past 1 year or undergoing extra screening for recurrence

         12. Planned surgery within the following 12 weeks

         13. Planning to move with the following next 12 weeks

         14. Participating in another clinical trial with an experimental medication.

         15. Alcohol or substance abuse, or any other condition that in the investigator's opinion
             would make the patient unsuitable for this study.

         16. A history of allergic or anaphylactic reaction to NAC, or any component of the
             preparation.

         17. Clinically unstable medical or psychiatric disorders that require acute treatment.

         18. Active gastrointestinal ulcers.

         19. Subjects taking concomitant medications or supplements known for their glutamatergic
             effects (e.g., dextromethorphan, D-cycloserine, memantine, lamotrigine, riluzole),
             antioxidant properties (DMG, TMG, other alternative treatments), or medications with
             an effect on sleepiness and possibly fatigue such as Provigil, Nuvigil and amantadine
             within 2 weeks of the baseline visit with the exception of short-term use of
             dextromethorphan as needed as a cough suppressant. Regular multivitamins will be
             allowed.

         20. Patients taking anticoagulants

         21. Patients with history of obvious secondary causes of fatigue, such as chronic
             insomnia, sleep apnea, narcolepsy, restless leg syndrome and significant bladder
             dysfunction disrupting sleep.

         22. Screening Epworth Sleepiness Scale score greater than 15.

         23. Starting or changing the dose of benzodiazepine, antidepressant, antipsychotics,
             anti-histamines, or stimulants within a month from the screening visit.

         24. A score of 15 or greater on the Hospital Anxiety and Depression Scale (HADS)
             depression subscale.

         25. Patients currently treated for asthma.