A Study of Oxidative Pathways in MS Fatigue
Condition: Progressive Multiple Sclerosis; Fatigue
MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Sclerosis; Fatigue
Study type: Interventional
Phase: Phase 2

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.
    

Detailed description: 
      1Background 1.1 Multiple Sclerosis Multiple sclerosis is the most common cause of
      non-traumatic disability in young adults in the US. It is an inflammatory, demyelinating and
      neurodegenerative disease of the central nervous system. Patients with MS often experience
      various types of disabling symptoms such as chronic fatigue or pain. Most patients with an
      initial relapsing-remitting course develop at some point insidious disability worsening, i.e.
      secondary progressive MS. In contrast, about 15% of multiple sclerosis patients experience an
      insidiously progressive course from onset. Primary and secondary progressive multiple
      sclerosis is thought to have similar physiopathology. As such, strategies for managing
      symptoms of relapsing patients may not necessarily apply to those with progressive disease;
      however, most symptomatic treatment trials have been done in relapsing-remitting or mixed
      populations of patients, neglecting a large fraction of patients with progressive forms of
      the disease. Investigator is planning to address an important clinical and pathophysiologic
      issue in this proposed study.

      1.2 Fatigue in multiple sclerosis Fatigue as defined by a subjective lack of physical or
      mental energy perceived by the individual with usual activities is the most common and
      disabling symptom of multiple sclerosis. Fatigue severity is not correlated with depression
      or neurological disability. It can impact substantially physical and cognitive activities and
      thus, negatively affect the quality of life of many patients. There are no medications
      specifically approved for fatigue in multiple sclerosis. Many chronic inflammatory disorders
      are associated with fatigue and peripheral inflammation is postulated to be an important
      contributor to fatigue pathogenesis. A spectroscopy study has reported decreased
      N-acetylaspartate/creatine ratio in several brain regions, thus all pointing at axonal loss
      as a possible contributing factor . In a cross-sectional relapsing-remitting MS study,
      fatigued patients had more severe atrophy of the striatum, thalamus and frontal and parietal
      gyri as compared to non-fatigued patients.

      As a direct consequence of the unknown pathophysiology, very little pharmacologic
      intervention is available for fatigue in multiple sclerosis. Glutamate, a critical
      neurotransmitter implicated in excitotoxicity and neurodegeneration, may also play a role in
      fatigue genesis. Two studies of a glutamate receptor antagonist (memantine) have reported
      worsening of fatigue in multiple sclerosis patients. In addition, Investigator have found
      that compared to placebo, riluzole (a medication with some anti-glutamate activity) worsened
      fatigue in patients with very early multiple sclerosis. This is in sharp contrast with the
      pathological evidence suggesting that excessive glutamate transmission may be a final
      effector in neuronal and axonal degeneration in multiple sclerosis animal models. Oxidative
      stress due to disequilibrium between oxidants and antioxidants in the central nervous system
      may also be a major contributor to neurodegeneration . It is unknown if oxidative stress
      plays a role in the pathogenesis of fatigue in multiple sclerosis.

      1.3 Fatigue rating scales Most of the fatigue scales used in multiple sclerosis studies were
      primarily developed and validated for use in other medical conditions. The two widely used
      self-completed scales in multiple sclerosis research are the Fatigue Severity Scale, and the
      Modified Fatigue Impact Scale.

      1.3a. Fatigue Severity Scale: This scale was originally designed to identify the common
      features of fatigue in multiple sclerosis, and lupus patients. It assesses the impact of
      fatigue on several outcomes, with an emphasis on physical fatigue. It is composed of 9
      questions with responses provided on a 7-point Likert scale. Scale score is the mean of the
      item scores and higher scores indicate more severe fatigue.

      1.3b.Modified Fatigue Impact Scale: This scale has been proposed by the Multiple Sclerosis
      Council for Clinical Practice Guidelines as the instrument of choice for assessing fatigue in
      multiple sclerosis. It is derived from the 40-item Fatigue Impact Scale. It has 21 items and
      assesses more dimensions of fatigue than the Fatigue Severity Scale: physical (9 items),
      cognitive (10 items) and psychosocial (2 items). The scale score is the sum of the 21 items
      and higher score indicates more severe fatigue. The scale has shown good reproducibility,
      ease of use and good correlation with fatigue severity scale scores. A cut-off value of 38
      distinguishes fatigued from non-fatigued multiple sclerosis patients.

      2.Rationale 2.1 Effect of N-acetyl cysteine in MS fatigue N-acetyl cysteine is an orally
      bioavailable precursor of the amino acid cysteine and is used to treat acetaminophen-induced
      hepatotoxicity. The medication half-life in adults is about 5.6 hours. As such it has been
      given twice or three times a day in various trials that have documented a biological effect.
      It protects the liver by restoring hepatic concentrations of cysteine and glutathione (GSH- a
      major intracellular antioxidant). Besides antioxidant properties, N-acetyl cysteine, by
      increasing the intracellular concentration of cysteine and activating the glutamate-cysteine
      antiporter eventually decreases glutamatergic transmission. Hypothetically, by decreasing
      excitotoxicity, it may protect neurons in different models of neuronal damage and
      neurodegeneration. Excellent safety profile and potential neuroprotective properties make
      N-acetyl cysteine an attractive target for examining its anti-fatigue properties in patients
      with progressive multiple sclerosis. Orally administered N-acetyl cysteine produces
      biologically relevant cerebrospinal fluid concentrations of N-acetyl cysteine at doses that
      are well tolerated. One study showed an effect of a single injection of N-acetyl cysteine on
      blood glutathione redox ratios followed by changes in glutathione concentration in the brain
      using 7T magnetic resonance spectroscopy in 3 patients with Parkinson's disease and 3
      controls.

      Clinical trials of oral N-acetyl cysteine for a wide variety of clinical conditions have used
      a range of different daily doses (from 600 mg to 6000 mg per day). The study investigator
      chose the daily dose of 3750 mg (1250 mg administered three times a day), based on its good
      tolerability, treatment compliance and minimum adverse effects reported in a recent clinical
      trial.

      2.2 Reason for using a placebo group

      There are no FDA-approved treatments for fatigue in multiple sclerosis. There are also no
      standard of care as various trials have reported inconsistent findings about the effect of
      amantadine in multiple sclerosis fatigue. Pursuant to the Helsinki Declaration, when standard
      treatment of a disease exists, placebo should generally not be used in clinical trials.
      However, Declaration of Helsinki supports the stance that placebo can be acceptable in the
      setting where no proven standard therapy exists:

      The benefits, risks, burdens and effectiveness of a new intervention must be tested against
      those of the best current proven intervention, except in the following circumstances:

        -  The use of placebo, or no treatment, is acceptable in studies where no current proven
           intervention exists; or

        -  Where for compelling and scientifically sound methodological reasons the use of placebo
           is necessary to determine the efficacy or safety of an intervention and the patients who
           receive placebo or no treatment will not be subject to any risk of serious or
           irreversible harm.

      2.3 Gap in fatigue management Symptomatic treatment trials for fatigue have been small,
      underpowered and with methodological flaws. As such, drawing firm conclusions and making
      therapeutic recommendations has been difficult. Thus, fatigue in multiple sclerosis remains
      very difficult to manage despite its substantial impact on patients' life. An issue when
      studying fatigue in patients with relapsing-remitting multiple sclerosis has been the
      possibility of increased fatigue during disease relapses and with specific disease-modifying
      therapies such as interferon. There has been no study focusing on the effects of drug therapy
      in fatigue in patients with progressive disease. Furthermore, study investigator's knowledge
      regarding the underlying pathophysiology of fatigue in multiple sclerosis is scarce and
      future studies of intervention on fatigue should include biomarkers to further elucidate the
      potential mechanisms of observed effects.

      The study investigator hypothesize that fatigue in progressive multiple sclerosis patients is
      associated with increased glutamate and decreased glutathione concentration on brain
      spectroscopy at baseline. The study investigator also hypothesize that fatigue is associated
      with changes of various oxidative pathway metabolites in peripheral blood.

      4. Study Design 4.1 Overview of study design: 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 multiple sclerosis defined by
      McDonald criteria. Subjects, who enter the treatment phase of study, will be randomly
      assigned to either N-acetyl cysteine (1250mg 3 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 2hours of morning dose of study medication. Questionnaires, and research
      samples will be obtained before neurological exam or magnetic resonance imaging. Research
      blood draws will be obtained just after questionnaire completion. Brain spectroscopy will be
      obtained less than 2hours after morning dose of study drug to maximize detection of the
      biological effect of study medication.

      4.2 Enrollment sites Enrollment will start in August, 2016. Enrollment period will last 6
      months. Patients will be enrolled in the trial at University of California San Francisco.

      4.3 Study visits 4.3a Screening period: Total duration of screening period is 4 weeks. An
      additional 5 patients with progressive multiple sclerosis who volunteered for participation
      in the clinical trial, but had a screening modified fatigue impact scale score of <38 or were
      recruited from site's clinic (who reported no fatigue and their fatigue scale score was <38),
      will undergo brain imaging on 7Tesla magnetic resonance imaging machine, and research blood
      draws.

      4.3b Treatment period: Total duration of the blinded treatment period is 4 weeks. After the
      screening visit, the inclusion/ exclusion criteria details of eligible patients will be
      reviewed by study investigator. The eligible study participants will be randomized in
      approximately a 2:1 ratio to one of the two arms of either N-acetyl cysteine or placebo. The
      treatment group assignment will be blinded for the duration of the study. A week-2 phone
      visit will be completed to determine the tolerance of study drug.

      4.3c Follow up phone visit: Two weeks after taking the last dose of study medication, fatigue
      scale questionnaires are completed over phone by the study coordinator to collect the safety
      and efficacy measures of the study. Additional phone visit needs to be completed 2 weeks from
      randomization to assess the safety, tolerability, and compliance of study medication.

      4.5 Study visit window: The screening period can be up to 4 weeks. The baseline visits needs
      to be completed within 28 days of screening visit. Week 2 phone visit in +/- 5 days of Day
      14, and week 4visit in Day 28+/-7 days of baseline. Follow-up phone call is completed +/- 5
      days of week 6 visit.
    

Intervention name(s): N-acetyl cysteine; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 1250 mg of N- acetyl cysteine taken three times daily; placebo taken three times daily
Other intervention name(s): NAC
Intervention MeSH terms: Acetylcysteine; N-monoacetylcystine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment