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A pilot study of oxidative pathways in MS fatigue: randomized trial of N-acetyl cysteine.

  • 2021-03-06
  • Annals of clinical and translational neurology 8(4)
    • Kristen M Krysko
    • Antje Bischof
    • Bardia Nourbakhsh
    • Roland G Henry
    • Nisha Revirajan
    • Michael Manguinao
    • Khang Nguyen
    • Amit Akula
    • Yan Li
    • Emmanuelle Waubant

Study Design

Type
Randomized Controlled Trial (RCT)
Population
Individuals with progressive MS with Modified Fatigue Impact Scale (MFIS) > 38
Methods
Randomized 2:1 to NAC 1250mg TID or placebo for 4 weeks
Blinding
Double-blind
Duration
4 weeks
Funding
Unclear

Objective

To assess feasibility, tolerability, and safety of N-acetyl cysteine (NAC) for fatigue in progressive MS. Secondary objectives evaluated changes in fatigue and oxidative pathway biomarkers on NAC versus placebo.

Methods

Individuals with progressive MS with Modified Fatigue Impact Scale (MFIS) > t38 were randomized 2:1 to NAC 1250mg TID or placebo for 4 weeks. The primary outcome was tolerability and safety. The secondary outcome to evaluate efficacy was MFIS change from baseline to week 4 between groups. Exploratory biomarker outcomes included change in blood GSH/GSSG ratio (reduced-to-oxidized glutathione (GSH)) and in vivo relative GSH using 7T MR spectroscopy (MRS) between groups. Fisher exact test was used for categorical and rank sum for continuous outcomes.

Results

Fifiteen were randomized (10 NAC, 5 placebo; mean age 56.1 years, 80% female, median EDSS 6.0). At least one adverse event (AE) occurred in 60% on NAC versus 80% on placebo (p = 0.75). There were two AEs attributed to NAC in one patient (abdominal pain and constipation), with 94% adherence to NAC. MFIS decreased in both groups at week 4, with the mean improvement of 11-points on NAC versus 18-points on placebo (p = 0.33). GSH/GSSG ratio decreased on placebo (-0.6) and NAC (-0.1) (p = 0.18). Change in GSH levels to total creatine in anterior and posterior cingulate cortex, insula, caudate, putamen, and thalamus did not differ between groups.

Interpretation

NAC was well-tolerated in progressive MS, although reduction in fatigue on NAC was similar to placebo. Antioxidant blood and MRS biomarkers were not significantly altered by NAC, which could be due to dose, route of administration, time of sample collection, short half-life, or lack of effect. REGISTERED: clinicaltrials.gov NCT02804594.

Research Insights

  • N-Acetyl Cysteine→Increased Brain Glutathione Level

    Change in GSH levels to total creatine in anterior and posterior cingulate cortex, insula, caudate, putamen, and thalamus did not differ between groups.

    Effect
    Neutral
    Effect size
    Small
    Dose
    1250 mg three times daily (TID)
  • N-Acetyl Cysteine→Increased GSH/GSSG Ratio

    GSH/GSSG ratio decreased on placebo (-0.6) and NAC (-0.1) (p = 0.18).

    Effect
    Neutral
    Effect size
    Small
    Dose
    1250 mg three times daily (TID)
  • N-Acetyl Cysteine→Reduced Fatigue

    MFIS decreased in both groups at week 4, with the mean improvement of 11-points on NAC versus 18-points on placebo (p = 0.33).

    Effect
    Neutral
    Effect size
    Small
    Dose
    1250 mg three times daily (TID)

Adverse Events Reported

  • N-Acetyl Cysteine→Overall tolerability

    At least one adverse event (AE) occurred in 60% on NAC versus 80% on placebo (p = 0.75).

    Finding
    No significant difference
    Magnitude
    60% on NAC versus 80% on placebo (p = 0.75)
    Significant
    No
  • N-Acetyl Cysteine→abdominal pain

    There were two AEs attributed to NAC in one patient (abdominal pain and constipation)

    Finding
    Reported
  • N-Acetyl Cysteine→constipation

    There were two AEs attributed to NAC in one patient (abdominal pain and constipation)

    Finding
    Reported
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