A Phase 2 Randomized, Placebo- Controlled, Parallel Group, Double Blinded Single Center Study on Effect of N-acetyl Cysteine Compared to Placebo on Fatigue in Patients With Progressive Multiple Sclerosis

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.