Fatigue in Multiple SclerosisPhase 2NCT02286557
Testing the Effects of Methylphenidate on Multiple Sclerosis
A Phase 2 study testing Methelphenidate in people with Fatigue in Multiple Sclerosis, run by Kessler Foundation at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Fatigue in Multiple Sclerosis
- What is being tested?
- Methelphenidate
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 36 participants
- Where
- 1 siteUnited States
- Study dates
- Oct 2014to 4 Mar 2025
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Diagnosis of Multiple Sclerosis
- Age: 18-65 years old
Who cannot join
- Participants must be free of: corticosteroids, cannot be currently taking modafinil, amantadine or other psychostimulants.
- Participants must be MS relapse free at least during the previous 4 weeks.
- Participants cannot consume more than ≧300mg of caffeine per day.
- Thyroid disease
- Anemia
- Decreased vitamin D.
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read the detailed description
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.
- Conditions
- Fatigue in Multiple Sclerosis
- Being tested
- Methelphenidate, Placebo
- Keywords
- Methylphenidate, Multiple Sclerosis, Cognitive Fatigue
- Medical subject headings
- Multiple Sclerosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MethelphenidateDrug
All participants will undergo 4 weeks of treatment with Methelphenidate and 4 weeks of placebo
PlaceboDrug
| Study group | Role | What they receive |
|---|---|---|
| Arm I | Experimental | Arm 1 will undergo four weeks of treatment with MP extended-release (20 mg/day in the morning). Following the four weeks of treatment, all assessments performed at baseline will be repeated. To minimize practice effects, alternate versions of the neuropsychological tests will be used wherever available. A 7-day washout period will follow in which no medication will be administered. Following the washout period, Arm 1 will undergo four weeks of placebo. This will be followed by a final assessment consisting of measures of fatigue, cognitive functioning, and physical disability. Receives: Drug: Methelphenidate; Drug: Placebo |
| Arm II | Experimental | Arm 2 will undergo four weeks of placebo (in the morning). Following the four weeks of placebo, all assessments performed at baseline will be repeated. To minimize practice effects, alternate versions of the neuropsychological tests will be used wherever available. A 7-day washout period will follow in which no medication will be administered. Following the washout period, Arm 2 will undergo four weeks of treatment with MP extended-release (20mg/day). This will be followed by a final assessment consisting of measures of fatigue, sleep quality, cognitive functioning, and physical disability. Receives: Drug: Methelphenidate; Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Fatigue - Modified Fatigue Impact Scale
Changes on fatigue levels from baseline, will be assess after 4 weeks, and after 10 weeks of the duration of the study.
Measured: baseline, day 30 and day 68
Secondary outcomes (1)
Processing Speed - Symbol Digit Modalities Test
Changes on Processing speed from baseline, will be assess after 4 weeks, and after 10 weeks of the duration of the study.
Measured: baseline, day 30 and day 68
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Nov 2014 (estimated)
- Study startOct 2014
- Primary completion28 Feb 2025
- Study completion4 Mar 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Fatigue in Multiple SclerosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 36 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Kessler Foundation
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Silvana Costa, Kessler Foundation
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02286557
- Sponsor's protocol ID
- PP2280
- Status last verified
- Aug 2025
- First submitted
- 16 Oct 2014
- Last updated
- 2 Sep 2025
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 2 Sep 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Testing the Effects of Methylphenidate on Cognitive Fatigue in Multiple Sclerosis: a Double-blind, Placebo-controlled, Randomized Clinical Trial
- ClinicalTrials.gov ID
- NCT02286557
- Acronym / sponsor ID
- PP2280
- Conditions
- Fatigue in Multiple Sclerosis
- Keywords
- Methylphenidate, Multiple Sclerosis, Cognitive Fatigue
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 36 participants (estimated)
- Lead sponsor
- Kessler FoundationUniversity, hospital or other
- Study start
- Oct 2014
- Primary completion
- 28 Feb 2025 (actual)
- Study completion
- 4 Mar 2025 (actual)
- First posted
- 10 Nov 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Arm I | Experimental | Drug: Methelphenidate, Drug: PlaceboArm 1 will undergo four weeks of treatment with MP extended-release (20 mg/day in the morning). Following the four weeks of treatment, all assessments performed at baseline will be repeated. To minimize practice effects, alternate versions of the neuropsychological tests will be used wherever available. A 7-day washout period will follow in which no medication will be administered. Following the washout period, Arm 1 will undergo four weeks of placebo. This will be followed by a final assessment consisting of measures of fatigue, cognitive functioning, and physical disability. |
| Arm II | Experimental | Drug: Methelphenidate, Drug: PlaceboArm 2 will undergo four weeks of placebo (in the morning). Following the four weeks of placebo, all assessments performed at baseline will be repeated. To minimize practice effects, alternate versions of the neuropsychological tests will be used wherever available. A 7-day washout period will follow in which no medication will be administered. Following the washout period, Arm 2 will undergo four weeks of treatment with MP extended-release (20mg/day). This will be followed by a final assessment consisting of measures of fatigue, sleep quality, cognitive functioning, and physical disability. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- Diagnosis of Multiple Sclerosis
- Age: 18-65 years old
Key exclusion criteria (6 listed)
- Participants must be free of: corticosteroids, cannot be currently taking modafinil, amantadine or other psychostimulants.
- Participants must be MS relapse free at least during the previous 4 weeks.
- Participants cannot consume more than ≧300mg of caffeine per day.
- Thyroid disease
- Anemia
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MethelphenidateAll participants will undergo 4 weeks of treatment with Methelphenidate and 4 weeks of placebo | Drug | Arm I, Arm II |
| Placebo | Drug | Arm I, Arm II |
Primary outcome
Fatigue - Modified Fatigue Impact Scale
Time frame: baseline, day 30 and day 68
Changes on fatigue levels from baseline, will be assess after 4 weeks, and after 10 weeks of the duration of the study.
1 secondary outcome
Processing Speed - Symbol Digit Modalities Test
Time frame: baseline, day 30 and day 68
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Sep 2025.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Methelphenidate in people with Fatigue in Multiple Sclerosis, run by Kessler Foundation at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 2 Sep 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Fatigue - Modified Fatigue Impact Scale (time frame: baseline, day 30 and day 68). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Sep 2025; AzTrials last refreshed its copy on 29 Oct 2026.