Fatigue in Multiple Sclerosis Clinical Trial
Official title:
Testing the Effects of Methylphenidate on Cognitive Fatigue in Multiple Sclerosis: a Double-blind, Placebo-controlled, Randomized Clinical Trial
Up to 95% of individuals with Multiple Sclerosis report experiencing cognitive fatigue,
characterized by a lack of energy, feelings of exhaustion, an the perception that one is
unable to partake in daily activities. The goal of this project is to test whether
methylphenidate (MP), a well-known psychostimulant, can effective treat fatigue experienced
by individuals with MS.
The current study will test the effect of MP on MS fatigue through a clinical trial. Every
participant in the study will be exposed to both the drug and the placebo for a period of
time. Both the investigators and participants will be unaware whether participants are
receiving the drug or the placebo.
Upon successful completion of the study, physicians will be able to evaluate the potential
prescription of MP to treat fatigue in persons with MS based on solid research evidence.
Importantly, MP is already an FDA approved widely used medication in multiple clinical
populations.
As highlighted by the National Clinical Advisory Board of the National Multiple Sclerosis
Society (NMSS), "fatigue is the most common MS (multiple sclerosis) symptom", affecting up
to 95% of individuals. Higher levels of cognitive fatigue have been associated with poorer
quality of life (Amato & Portaccio, 2012) and increased disability (Lapierre & Hum, 2007),
negatively affecting wellness. Several medications are currently prescribed to individuals
with MS who suffer from fatigue, such as amantadine and modafinil. However, the effect of
these medications on decreasing fatigue levels in individuals with MS is suboptimal (e.g.
Stankoff et al., 2005). At the same time, there is overwhelming evidence showing that
methylphenidate is effective at relieving fatigue in individuals with cancer (Minton et al.,
2013), human immunodeficiency virus (Breitbart, Rosenfeld, Kaim, & Funesti-Esch, 2001),
Parkinson's disease (Devos et al., 2013) and chronic fatigue syndrome (CFS) (Blockmans et
al., 2006). For example, individuals with CFS reported decreased fatigue levels (as measured
with a visual analogue scale) when taking MP (Blockmans et al., 2006). Although MP has been
demonstrated to be an effective fatigue-relieving drug in multiple clinical populations
discussed above, the effect of MP on MS-related fatigue has not been objectively tested.
MP is a psychostimulant that acts by inhibiting presynaptic dopamine transporters leading to
suppression of dopamine reuptake (Prommer, 2012). That is, due to reuptake suppression, more
dopamine remains in the synapses. MP primarily affects the striatum (which receives dopamine
neuron projections from the substantia nigra pars compacta) and subsequently the prefrontal
cortex (PFC), which receives dopaminergic projections from the striatum (Volkow et al.,
2001).
To our knowledge, the only randomized clinical trial using MP in persons with MS assessed
the effect of this medication on attention, reporting significant improvements in cognitive
task performance (PASAT) in the MP treatment group (Harel, Appleboim, Lavie, & Achiron,
2009) as compared to a placebo control group. While an expert opinion paper sponsored by the
NMSS recommends the use of MP to treat fatigue (Expert Opinion Paper, 2006), to our
knowledge, no clinical trials have been conduced to objectively test the effect of MP
administration on fatigue in individuals with MS and support this recommendation. The
current study will fill this void in the literature. Aim 1: We propose to test the efficacy
of MP on decreasing self-reported fatigue in individuals with MS in a double blind placebo
controlled randomized clinical trial (DBRCT). Aim 2: We will also examine the effects of MP
on cognitive functioning. Based on the existing literature on MP (Bales, Wagner, Kline, &
Dixon, 2009; Harel et al., 2009), we expect that MP will enhance processing speed and
attention, with little impact on other cognitive functions such as memory or executive
control.
Significance: Our DBRCT will be the first to empirically assess the efficacy of MP as a
treatment of MS-related fatigue. The application of the stringent RCT methodology will
result in Class I evidence supporting or refuting the efficacy MP as a fatigue-relieving
drug. The amelioration of fatigue in MS will have a significant positive impact on the MS
population, given the prevalence and negative effects of fatigue.
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment
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