An official website of the United States government
NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
Bardia Nourbakhsh, MD, MAS, Nisha Revirajan, MBBS, Bridget Morris, MSN, Christian Cordano, MD, PhD, Jennifer Creasman, MSPH, Michael Manguinao, BS, Krysten Krysko, MD, MAS, Alice Rutatangwa, DO, Caroline Auvray, MD, Salman Aljarallah, MBBS, Chengshi Jin, PhD, Ellen Mowry, MD, MCR, Charles McCulloch, PhD, and Emmanuelle Waubant, MD, PhD.
Author Information and AffiliationsFatigue is the most common symptom of multiple sclerosis (MS) and a significant cause of disability, unemployment, and decreased quality of life (QOL) in patients with the disease. Although the FDA has approved no drugs for the treatment of MS-related fatigue, clinicians commonly prescribe amantadine, modafinil, and amphetamine-like psychostimulants (such as methylphenidate) to alleviate fatigue. The evidence supporting these medications' efficacy is sparse and conflicting, and their comparative effectiveness is not known.
We sought to determine the effect of treatment with amantadine vs modafinil vs methylphenidate vs placebo on MS fatigue, fatigue-related QOL, and sleepiness, as well as the short-term safety and tolerability of these medications.
In a 2-center, randomized, double-blind, placebo-controlled, 4-sequence, 4-period crossover trial, patients with MS and fatigue received twice-daily oral amantadine (up to 200 mg daily), modafinil (up to 200 mg daily), and methylphenidate (up to 20 mg daily), each given for 6 weeks. The primary outcome measure was the Modified Fatigue Impact Scale (MFIS), measured while taking the maximum or highest tolerated dose of each medication. Secondary outcomes included measures of sleepiness, fatigue-related QOL, adverse effects, and the maximally tolerated dose of each drug. We used linear mixed-effect regression models for efficacy analyses.
A total of 141 patients were enrolled and randomly assigned to 1 of 4 sequences for taking the 4 interventions. Data from 136 participants were available for the intention-to-treat analysis of the primary outcome. The estimated mean values of MFIS total scores (95% CI) at baseline and at the maximum tolerated dose were as follows: 51.3 (49.0-53.6) at baseline, 40.6 (38.2-43.1) with placebo, 41.3 (38.8-43.7) with amantadine, 39.0 (36.6-41.4) with modafinil, and 38.6 (36.2-41.0) with methylphenidate (P = .20 for the overall medication effect in the linear mixed-effect regression model). Compared with placebo (30.6%), higher proportions of participants reported adverse events (AEs) while taking amantadine (38.6%), modafinil (40.0%), and methylphenidate (39.5%).
Amantadine, modafinil, and methylphenidate were not superior to placebo in improving MS-related fatigue and caused more frequent AEs. The results of this study do not support an indiscriminate use of amantadine, modafinil, or methylphenidate for the treatment of fatigue in MS.
The crossover study design might have resulted in a carryover effect that could not be adequately controlled in the statistical models. The fluctuation of fatigue levels during the study would have created nondifferential misclassification of outcome, which could have biased the results toward the null (no medication effect). The results are applicable only to the short-term impact of the studied medications on fatigue in MS. Because of the limits on drug dose and the short treatment period, we cannot rule out that the results might have been different with long-term use and higher doses of study drugs.
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) that results in demyelination and neurodegeneration; it is the most common medical cause of disability in young adults.1 MS affects more than 900 000 people in the United States.2 Relapsing-remitting focal neurologic deficits and progressive decline of walking function are the hallmark symptoms of MS; however, patients with MS also experience a variety of other chronic symptoms. Fatigue, as defined by a subjective lack of physical or mental energy perceived by the individual with usual activities, is in fact the most common and one of the most disabling symptoms of MS.3-5 It is a significant contributor to reduced quality of life (QOL) in patients with MS,6 affecting their daily activities and resulting in loss of work hours, unemployment, and major socioeconomic consequences.7 MS-related fatigue has a complex and multifactorial pathophysiology. Immunologic changes and CNS damage are probably the major contributors to fatigue development, but other common conditions in MS, such as depression and sleep problems (eg, because of leg spasms and bladder dysfunction) add to the fatigue burden.8
Despite the prevalence and large negative impact of fatigue, treatments for it have been inconsistently studied. Complex pathophysiology and lack of a suitable animal model, clear treatment targets, measurement tools, or biomarkers have contributed to this problem. Although behavioral treatments (such cognitive behavior therapy) have been shown to be effective in improving fatigue in MS,9 many patients and clinicians, even in tertiary care centers, do not have access to these treatments and thus resort to medications to help with this chronic and disabling symptom, despite the fact that the FDA has approved no medications for the treatment of MS fatigue. Nevertheless, the off-label use of several medications for fatigue treatment is common in clinical practice.8,10 Most of these medications have been tested in clinical trials or observational studies for the treatment of fatigue in MS or other medical conditions, but methodologic limitations in the design, execution, and reporting of those studies do not allow firm conclusions to be drawn about their efficacy.11,12 Comparative effectiveness trials have been small and yielded inconsistent results.13-15 The most common medications prescribed by clinicians for treatment of MS fatigue are amantadine; wake-promoting agents, such as modafinil; and amphetamine-like psychostimulants,8,10 such as methylphenidate.
Amantadine, a medication that is FDA approved for the prophylaxis of influenza and symptomatic treatment of Parkinson disease, is a commonly used and widely studied medication for MS fatigue. It has pleiotropic effects on the glutamatergic, dopaminergic, and cholinergic systems in the CNS.16 There have been multiple clinical trials of amantadine for the treatment of MS fatigue,13,15,17-20 but because of methodologic problems and conflicting results, a Cochrane systematic review concluded that the efficacy of amantadine in treating MS fatigue was poorly documented and emphasized the need for good-quality randomized trials.11
Modafinil, an FDA-approved medication for narcolepsy, obstructive sleep apnea, and shift work sleep disorder, is a nonamphetamine wake-promoting agent.21 Clinicians prescribe it commonly as an off-label treatment for MS fatigue. It has been tested for this condition in several randomized controlled trials (RCTs),13,22 but a systematic review concluded that clinical trials had provided inconsistent results.23
Amphetamine-like psychostimulants have been tested and used for fatigue treatment in various medical conditions. Despite their widespread prescription for treatment of MS fatigue, there is minimal evidence for efficacy in this condition. The only RCT of a psychostimulant for MS fatigue tested pemoline, a medication that is currently not available in the United States.24 That study showed that pemoline improved MS fatigue but was poorly tolerated. Lisdexamfetamine, another amphetamine-like stimulant, improved processing speed and memory in cognitively impaired patients with MS, but it did not affect fatigue severity in a phase 2 RCT.25 Methylphenidate, another amphetamine-like psychostimulant that is FDA approved for the treatment of attention-deficit/hyperactivity disorder (ADHD), has been studied in several RCTs of fatigue in conditions other than MS.26-29 The results of those studies were inconsistent. Despite the lack of evidence, methylphenidate is commonly prescribed for the treatment of MS fatigue.
As we reviewed in this section, fatigue is a common and disabling symptom of MS. There is no FDA-approved medication for fatigue treatment, and the medications that are commonly used as off-label therapies (such as amantadine, modafinil, and methylphenidate) have no or conflicting evidence supporting their use. Also, no prior studies have compared these 3 medications against each other.
The aims of this pragmatic RCT were to demonstrate the efficacy (or lack thereof) of amantadine, modafinil, and methylphenidate compared with placebo in alleviating MS-related fatigue; compare the efficacy of these 3 medications with each other; and understand their adverse effects and tolerability. Because these medications are available in most practice settings and are relatively affordable for many patients, the results of this study will be readily translated into evidence-based treatment of fatigue, the most common MS symptom. In addition, the results will improve patient outcomes and reduce the incidence of unwarranted adverse effects of less (or not) efficacious medications.
In an attempt to perform a patient-centered research project and according to PCORI methodology standards, we involved stakeholders in all aspects of this study. The main stakeholders in this clinical trial included (1) patients with MS, (2) community and academic neurologists taking care of patients with MS, (3) experts in the field of MS-related fatigue, and (4) the National Multiple Sclerosis Society (NMSS). These stakeholders were involved in planning and conducting the study and in disseminating its results.
The inception and planning of the proposed study resulted directly from feedback from patients with MS and their partners and family members about the detrimental effects of fatigue on their personal, social, and professional lives. The availability of disease-modifying therapies (DMTs) for MS in clinical practice has focused patients' and clinicians' attention on choosing appropriate treatment, optimizing its use, and managing adverse effects. Treatment of symptoms such as fatigue has become a secondary priority in busy neurology clinics in part as a result of the lack of clear evidence of a treatment effect and guidelines for selecting appropriate symptomatic treatment. These issues have been discussed with patients and families at our tertiary care subspecialty MS clinics because employment loss and the need for disability support are commonly related to untreatable fatigue. Many of these patients have, in fact, otherwise well-controlled disease activity on a DMT.
We also consulted 1 of our patients at the University of California San Francisco (UCSF) Multiple Sclerosis and Neuroinflammation Center regarding our proposed project. She had managerial positions in several large companies and had participated in several longitudinal studies of MS (including a clinical trial of a DMT) since being diagnosed with MS. Because of her experience and background, she was in a unique position to advise the research group on optimally planning and executing the study. She also joined our study advisory committee (SAC).
We formed a SAC consisting of 2 patients, an academic MS neurologist, a community MS neurologist, a behavioral neurologist, an expert in the field of MS-related fatigue, and a representative from the NMSS. The SAC had 1 in-person meeting before the start of the recruitment phase. The rest of the twice-a-year SAC meetings were conducted through conference calls and webinars.
The most crucial role of the SAC was to give recommendations regarding study protocol revisions. The SAC recommendations led to a revision of the eligibility criteria, frequency of contact with participants, and methods of collecting study outcomes (see the “Changes to the Original Study Protocol” section). The SAC was also involved in discussions regarding improvements to the recruitment process.
After completing recruitment, the discussions during the SAC conference calls were mostly centered around the methods for disseminating the study results. Through existing outreach efforts of the NMSS, such as newsletters, we will be able to reach large numbers of patients and clinicians and notify them of the study results. We will use the expertise of the NMSS in delivering complex medical and scientific information in an easily understandable format to patients and their families.
This study was a pragmatic, randomized, double-blind, 4-sequence, 4-period, crossover clinical trial aiming to determine the within-participant effect of treatment with amantadine vs modafinil vs methylphenidate vs placebo on fatigue (primary outcome), sleepiness, and fatigue-related QOL in patients with MS. We also aimed to assess the safety and tolerability of short-term treatment with these medications.
The study setting was 2 academic MS clinics in the United States (Johns Hopkins Multiple Sclerosis Center and UCSF Multiple Sclerosis and Neuroinflammation Center). These 2 centers provide care to patients with MS with diverse racial and ethnic backgrounds, socioeconomic status, MS subtypes, and levels of disability.
The target population was adult patients (men and women aged ≥18 years) with relapsing-remitting or progressive MS and fatigue. The majority of participants were patients who had their MS care established at either Johns Hopkins Multiple Sclerosis Center or UCSF Multiple Sclerosis and Neuroinflammation Center. Neurologists and other clinical providers at these MS centers introduced the opportunity to participate in this study to their patients who were potentially eligible (ie, had a diagnosis of MS and complained of fatigue) and referred them to the study teams. A small proportion of participants who heard about this study through other means (mostly online sources, such as ClinicalTrials.gov and the NMSS website or emails) contacted the study teams directly to be evaluated for participation.
We recorded the reasons patients declined to participate in the study or failed the screening process.
In this crossover trial, participants were randomly assigned to 1 of 4 medication sequences. A biostatistician at UCSF prepared 2 concealed allocation schedules (1 for each study site), randomly assigning the 4 sequences in blocks of 4 and 6 to a consecutive series of numbers. Only the study statistician and pharmacists at each site had access to the randomization tables, and all other study personnel and participants were blinded to the sequence of medication administration.
The following study eligibility criteria were chosen to maximize the generalizability of the results while taking into account the safety and well-being of the participants:
The trial had the following exclusion criteria:
As explained in the Background section, amantadine, modafinil, and psychostimulants are the most commonly used and studied medications for the treatment of fatigue in MS. Although they have been studied and used clinically for many years, their efficacy is still unclear, and there is no consensus among experts regarding their clinical utility. Here, we briefly review the medications that we have selected for the study to assess their effectiveness in the treatment of MS-related fatigue.
Amantadine is FDA approved for the prophylaxis of influenza and symptomatic treatment of Parkinson disease. It was the first medication tried for MS-related fatigue30 and is probably the most widely studied medication for this indication. Amantadine has anticholinergic properties, changes dopamine release in the striatum, and blocks the N-methyl-D-aspartate (NMDA) glutamate receptor.16 It is not clear which pharmacologic effect may be responsible for its possible antifatigue properties in MS. Despite multiple RCTs of amantadine for MS fatigue,13,15,17-20 methodologic issues and conflicting results have prevented any final conclusion on effectiveness. A Cochrane systematic review concluded that the efficacy of amantadine in treating MS fatigue is poorly documented and emphasized the need for good-quality RCTs.11 The most commonly reported adverse effects in reviewed trials were mild nausea and dizziness that did not require treatment.11,13,14 Considering its relative safety, wide availability, and conflicting evidence for efficacy, we chose amantadine as a comparator in this study. Amantadine is usually prescribed at 100 mg twice daily (total of 200 mg/day). We chose this dose as the maximum dose in this trial. Participants were started at 100 mg/day at the beginning of the amantadine medication period. The dose was increased to 200 mg/day (if tolerated) at the beginning of the third week. Participants continued on 200 mg/day during the fourth and fifth weeks of the medication period. To reduce the potential for withdrawal symptoms, we reduced the dose to 100 mg/day during the sixth (last) week of the medication period.
Modafinil is a nonamphetamine wakefulness-promoting agent that is FDA approved for the treatment of narcolepsy, obstructive sleep apnea, and shift work sleep disorder.21 Its mechanism of action is not clear; however, it is believed to have dual noradrenergic and dopaminergic properties and to increase cortical activity in the frontal lobes.31 Modafinil is the most frequently prescribed fatigue medication, as reported by patients participating in a global registry for MS research, treatment, and patient education (the North American Research Committee on Multiple Sclerosis [NARCOMS] survey).5 Three RCTs produced inconsistent results regarding the beneficial effects of modafinil in MS fatigue. While 2 RCTs reported no effects,13,22 another trial reported clear benefits.21 A systematic review of the effect of modafinil in the treatment of fatigue in MS and several other neurologic disorders concluded that clinical trials had provided inconsistent results.23 The most common treatment-related adverse effects included headache, nervousness, and nausea.32 Because modafinil is widely used in clinical practice to treat MS-related fatigue and is safe and relatively well tolerated, we chose it as a comparator in our pragmatic RCT. Although modafinil in various dosages has been tested for MS fatigue, 1 trial reported a beneficial effect at 200 mg/day, while 400 mg/day was not effective in reducing fatigue in MS. Based on these data, we chose 100 mg twice daily as the maximum dose of modafinil in this trial. Participants were started at 100 mg/day at the beginning of the modafinil medication period. The dose was increased to 200 mg/day (if tolerated) at the beginning of the third week. Participants continued on 200 mg/day during the fourth and fifth weeks of the medication period. To reduce the potential for withdrawal symptoms, the dose was reduced to 100 mg/day during the sixth (last) week of the medication period.
Psychostimulants have also been used for the treatment of fatigue in different chronic conditions. Methylphenidate is an amphetamine-like psychostimulant approved for the treatment of ADHD. It increases the level of monoamines in the synaptic cleft by enhancing their release and blocking their reuptake. Common adverse effects associated with methylphenidate include headache, nervousness, irritability, tremor, insomnia, anorexia, gastrointestinal upset, and heart palpitations.33 The risk of addiction is relatively low (<1%-3%).34 Methylphenidate has been tried in several RCTs of fatigue treatment in conditions other than MS.26-29 Interestingly, the results of those trials have also been conflicting. Despite the lack of rigorous evidence, methylphenidate is one of the commonly used and recommended medications for the treatment of fatigue in MS.35
The only RCT of psychostimulants in MS fatigue was performed using pemoline, a medication used for the treatment of ADHD.24 This study concluded that pemoline might be an effective short-term treatment for MS fatigue but is not well tolerated by many patients. This medication is, however, currently not available in the United States. The results of the trials of different doses of pemoline were also inconsistent.18,24
Because psychostimulants are widely used for the treatment of fatigue in MS and other chronic conditions, after consultation with several patients with MS and neurologists we decided to include an amphetamine-like stimulant as a comparator in our trial. We chose methylphenidate as a comparator because it has been tested in several clinical trials of fatigue in conditions other than MS and is an extensively used medication (for treatment of ADHD), with well-known side effects and safety profiles, and is inexpensive. To use methylphenidate safely in a large group of patients with MS using minimal exclusion criteria and supervision (to increase the pragmatic aspect of the study), we chose a maximum daily dose of 20 mg. Methylphenidate was initiated at 5 mg/day at the beginning of the medication period and was increased by 5 mg/week to the maximum daily dose of 20 mg during the fourth and fifth weeks of the medication period (if tolerated). To reduce possible withdrawal symptoms, we tapered down the dose to 10 mg/day during the sixth (last) week of the medication period before it was discontinued.
Amantadine, modafinil, and methylphenidate have been FDA approved for the treatment of several neurologic conditions for many years, and their safety profiles are well known. Because they are most commonly used for MS fatigue, we decided to assess and compare their effectiveness in MS-related fatigue in patients representative of the MS population in the United States. Based on the unclear efficacy of these medications, we concluded that the proposed trial should include a placebo treatment period. To compare the effectiveness of these medications against each other requires showing that at least 1 is superior to placebo in the first place. In the proposed study, we were powered to demonstrate the superiority of 1 (or more) of these medications to placebo and to compare their efficacy against each other. Placebo was made by filling an inert powder (microcrystalline cellulose PH-101) into capsule shells.
The duration of each treatment period (6 weeks) was chosen based on the assumption that the antifatigue effects of these medications were not delayed so that the full efficacy would be apparent after a few days of receiving the highest tolerated dose. A 6-week treatment period would allow safe titration, enabling us to measure trial outcomes on the highest tolerated dose and to safely taper doses at the end of the treatment period, thereby reducing the possibility of withdrawal symptoms.
We have included a minimum 2-week washout period between each treatment period, reducing the possibility of cross-contamination and carryover effects. The 2-week washout period was selected based on the elimination half-life of study medications (the maximum plasma half-life for the study medications was 31 hours for amantadine, and the other drugs had a shorter half-life)36-38 and the clinically observed putative antifatigue effects (which quickly disappear after stopping the medications).
The study was a randomized, crossover, 4-sequence, 4-period, double-blind (participants and investigators), multicenter trial of 3 commonly used medications (amantadine, modafinil, methylphenidate) for the treatment of MS-related fatigue vs placebo in patients with MS and fatigue. Using a balanced Latin square crossover design, we allocated participants, in a double-blind, randomized fashion, to 1 of the 4 treatment sequences (Figure 1): (1) amantadine, placebo, modafinil, and methylphenidate; (2) placebo, methylphenidate, amantadine, and modafinil; (3) modafinil, amantadine, methylphenidate, and placebo; and (4) methylphenidate, modafinil, placebo, and amantadine. Each treatment period was 6 weeks, with a 2-week washout period between each treatment period.
Study Design.
A biostatistician at UCSF prepared 2 concealed allocation schedules (1 for each study site), randomly assigning the 4 sequences in blocks of 4 and 6 to a consecutive series of numbers; at the time of enrollment, each participant was assigned the next consecutive number (and hence the sequence of study medications). Participants were randomly assigned to 1 of the above-mentioned treatment sequences in approximately a 1:1:1:1 ratio. Only the statistician building the allocation sequence and the pharmacists at each study site were aware of the study medication allocation sequence (ie, were unblinded). All other study personnel remained blinded to the allocation sequence until the study database lock. Participants were also blinded to their allocation sequence while actively participating in the study; however, after completing all the study procedures, they could contact the site pharmacist to find out their own medication sequence. We allowed this in order to help participants with their clinical care.
The primary efficacy outcome of the study was MFIS score. The MFIS score is a patient-reported outcome (PRO) that has been proposed by the MS Council for Clinical Practice Guidelines as the instrument of choice for assessing fatigue in MS. It was developed by the NMSS and derived from the 40-item FIS; it is also a component of the Multiple Sclerosis Quality of Life Inventory (MSQLI). The MFIS has 21 items and assesses more dimensions of fatigue than the other fatigue measures: physical (9 items), cognitive (10 items), and psychosocial (2 items). The patient rates the severity of each item on a scale of 0 to 4. The scale score is the sum of the scores for each of the 21 items, with a higher score indicating more severe fatigue. The minimum score is 0, and the maximum score is 84. The scale has shown good reproducibility, ease of use, and good correlation with Fatigue Severity Scale (FSS) scores.39 The MFIS also probably measures cognitive and psychosocial aspects of fatigue better than the FSS. The MFIS has a 28-day look-back period. The NMSS has recognized the MFIS as a valid and reliable measure of the impact of fatigue on activities of daily living in patients with MS.39 A Spanish version of the MFIS has been developed, and no cultural or linguistic differences were found in the psychometric properties of the Spanish version in patients with MS.40 The MFIS has been used as an end point in multiple clinical trials.22,41-43 The MFIS can be easily administered in person, on the web, and by phone, and it requires minimal or no guidance. It is possible to answer the questionnaire in less than 5 minutes.
At the time we designed the study, there were no data regarding what MFIS changes reflect objectively. In a study reported by Kos et al, a change of ≥10 points in MFIS score was considered to be clinically relevant.44 Since then, at least 1 publication, using anchor-based methods, reported a minimal important difference (MID) in the MFIS score change in patients with MS.45 MID estimates for MFIS ranged from 3.86 to 8.11 in MS, so a difference of at least 4 points on the scale constitutes a clinically significant difference in fatigue in patients with MS.
The Quality of Life in Neurological Disorders (Neuro-QoL) project was commissioned by the National Institute of Neurological Disorders and Stroke and has developed psychometrically robust and clinically relevant health-related QOL measures applicable across neurologic conditions.46,47 The psychometric properties of Neuro-QoL have been assessed in patients with MS.48,49 The Neuro-QoL fatigue item was administered as a computer-adaptive test. For all Neuro-QoL measures, scores are computed to a T-score metric. A T score of 50 is equivalent to the mean of the reference population (a large sample of neurologic patients). For Neuro-QoL fatigue item bank scores, higher scores indicate more severe fatigue. A 10-point difference indicates 1 SD from the mean (eg, a score of 40 indicates a level of outcome that is 1 SD above the mean). Neuro-QoL questionnaires have 7-day look-back periods. The MID for the Neuro-QoL fatigue item bank has not been reported in the literature.
The Epworth Sleepiness Scale (ESS) is a frequently used measure of patient-reported sleepiness in clinical neurology and sleep medicine. Sleepiness may be mistakenly considered synonymous with fatigue, but there is a complex relationship between these 2 conditions. Sleep problems may contribute to both daytime sleepiness and fatigue. Some of the prescribed medications for the treatment of fatigue (including modafinil and methylphenidate) have confirmed efficacy and FDA approval for the treatment of sleep disorders. Using the ESS, we can analyze the differential effect of the study medications on fatigue and sleepiness.
The ESS is a list of 8 situations in which participants rate their tendency to fall asleep on a scale of 0 to 3. The total score is based on a scale of 0 to 24, with higher scores denoting more severe sleepiness. The ESS does not have a clear look-back period. In patients with sleep apnea, using distribution- and anchor-based methods, the MID for the ESS has been estimated to be between 2 and 3 points. Scores >10 are considered compatible with excessive daytime sleepiness.
We asked the participants at the end of each treatment period about their satisfaction with the treatment: “Taking into consideration the possible benefits and/or disadvantages of this medication, would you choose it, going forward, to treat your MS fatigue?” Participants answered this question “yes” or “no.”
We analyzed the medication effects on the physical, cognitive, and psychosocial subscales of the MFIS. Based on the available data on the MID in MFIS change, we explored the medication effect on the proportion of participants who experienced a 4- or 10-point decrease in total MFIS score.
The assessment of safety was based on the frequency of adverse events (AEs). Tolerability was reported both as (1) the proportion of participants who achieved maximum dose and (2) the proportion of participants who discontinued the medication before the end of the treatment period. We also calculated the estimated average dose and 95% CIs by treating the maximum dose as the outcome in a mixed-model analysis (similar to the primary outcome analysis), with a single predictor of medication and with participants as a random effect.
The study end points were measured during the fifth week of each study period (while the participants were taking the highest or maximum tolerated dose of each study medication). All efficacy outcomes were questionnaires (PROs) administered remotely. Participants received an email containing the link to the study questionnaires. Clicking the link directed the participants to a secure online portal, enabling them to complete the questionnaires. By completing the questionnaires this way, the trial outcomes were captured directly in the study database. For participants who did not have access to the internet, we had planned to administer the questionnaires by phone or through the mail; however, all participants had internet access and could complete the questionnaires online.
The screening visit was the only in-person study visit. Screening visit procedures included a review of eligibility criteria; a physical examination; assessing EDSS scores; collecting vital signs and laboratory test results; and completion of the MFIS, Neuro-QoL fatigue item bank, and screening for depression by completing the Hospital Anxiety and Depression Scale (HADS) depression subscale The screening laboratory test results were collected if the screening visit MFIS score was >33. If the required laboratory tests were done within 30 days before screening and the results were available for review at the time of screening, the tests were not repeated (except for urine pregnancy test). Study participants were enrolled in the study after the site physician confirmed their eligibility. At this stage, participants were randomly assigned to 1 of 4 medication administration sequences (see Figure 1).
The study medication was dispensed by the site pharmacist to 1 of the study personnel. The study drug of the first assigned period was overnight-mailed to the participant. Alternatively, if eligibility was confirmed while the participant was still at the screening visit, the study team could randomly assign the participant and dispense the first-period medication. The baseline values of the primary and secondary outcomes were obtained through remote completion of PROs (web based for all participants, although phone or mailed paper forms were also available) within 3 days of initiating the first study drug. Participants started taking the study medication for the first period of their assigned sequence within 60 days after the screening visit. The schedule for study procedures and assessments is depicted in Table 1.
Schedule for Study Procedures and Assessments.
Patients who signed the informed consent form, but failed to meet eligibility criteria for enrollment, were deemed screen failures, and the reason for failure was documented on the screening log. Only demographic data, screening MFIS score, and the reason for screen failure were collected.
Study medications, which were compounded by the University of Iowa Pharmaceuticals, were provided as capsules, bottled, labeled, and shipped to each study site pharmacy. The pharmacist at each site (who had the randomization table provided by the study statistician) dispensed the study medication to the site coordinator based on the randomization number. Study personnel and participants remained blinded during all the study evaluations.
During each study period, participants received a bottle containing orange/red-colored capsules and a bottle containing blue-colored capsules. This plan was designed to keep the titration schedule for all treatment periods the same and keep participants and personnel blinded to treatment assignment.
For the amantadine treatment period, red-colored capsules contained amantadine 100 mg, and blue-colored capsules contained an inactive substance.
For the modafinil treatment period, red-colored capsules contained modafinil 100 mg, and blue-colored capsules contained an inactive substance.
For the methylphenidate treatment period, both red-colored and blue-colored capsules contained methylphenidate 5 mg.
For the placebo treatment period, both red-colored and blue-colored capsules contained an inactive substance.
Study medications were titrated according to Figure 2.
Schedule of Medication Titration During Study Medication Periods.
During all treatment periods, participants started taking 1 red-colored capsule in the morning for 1 week. At week 2, participants took 1 red-colored capsule and 1 blue-colored capsule in the morning. At the beginning of week 3, participants took 1 red-colored capsule and 1 blue-colored capsule in the morning and 1 red-colored capsule in the early afternoon. At the beginning of week 4, participants took 1 red-colored capsule and 1 blue-colored capsule in the morning and 1 red-colored capsule and 1 blue-colored capsule in the early afternoon. The week 5 dosing schedule was the same as for week 4. Beginning in week 6, participants tapered the medication and took 1 red-colored capsule and 1 blue-colored capsule in the morning. These instructions were mailed to the participants, along with the medication bottles.
The above dosing schedule was followed by participants who could tolerate the medication and dose titration. The study nurse or medical personnel called or contacted each participant (via email or text) at least 5 times during each treatment period and inquired about AEs, tolerability of study drug, and whether the dose could be increased. The schedule of phone calls (or emails or texts, depending on the participant's preference) is depicted in Table 2. If participants did not answer the phone calls (or emails or texts), it was assumed that they had experienced no AEs and could tolerate the medication titration according to the instructions provided to them. Aside from almost-weekly contact with the participants through phone calls, emails, or texts and inquiring about whether they took the medication, there was no other measure of adherence to the study intervention.
Schedule of Study Personnel Phone Calls (or Emails or Texts).
Participants could voluntarily withdraw from the study for any reason at any time. They were considered withdrawn if they stated an intention to withdraw; failed to return phone calls, emails, or texts; or did not complete their end-of-medication-period questionnaires or became lost to follow-up for any other reason.
If premature withdrawal occurred for any reason, the investigator team made every effort to determine and record the primary reason for a participant's premature withdrawal from the study.
Any participant who decided to stop the study medication because of the development of AEs was instructed by the study team to stop the study medication, and the outcome measures of that particular period were administered during the fifth week of that medication period (ie, within the scheduled time frame). For participants who stopped the study drug for at least 2 weeks and had answered the outcome questionnaires in week 5, the next medication period could be started immediately. If a participant decided to drop out and start a fatigue medication outside the study, the outcome questionnaires were administered while the participant was still taking the study medication or before he or she started a medication outside the study.
At the time we designed this trial, the only available report about the clinical relevance of a change in MFIS score was the study by Kos et al, 44 which considered a change of ≥10 points in MFIS score to be clinically relevant. We based the sample size calculation on detecting at least a 10-point difference between the placebo and medication groups and longitudinal measurements of the MFIS in patients with MS who participated in a trial of a putative neuroprotective agent. In that trial, frequent measurements of the MFIS had been obtained for up to 3 years: we found a between-subject variance of 330 points and within-subject variance of 80 points, with an intraclass correlation coefficient (ICC) of 0.80 (95% CI, 0.70-0.88). Using a more conservative ICC of 0.7, with a power of 90% and a type I error of .05 (corrected for 6 pairwise comparisons), we would have needed 91 participants (364 data points) to detect at least a 10-point difference in MFIS score between the placebo and study medication groups. Assuming 20% dropout after each treatment period, a sample size of 136 participants would provide the required number of data points. Post hoc calculations showed that the study had 80% power to detect a 4-point difference in the MFIS total score between the placebo and study medications.
We used REDCap (https://projectredcap.org),50 a secure web application for building and managing online surveys, collecting data, creating the trial database, and accessing the data for analysis. Most of the trial data (including baseline MFIS scores and questionnaires answered at the end of each study period) were directly captured via REDCap forms. If participants could not enter data online, phone calls or paper forms were available. Study coordinators, nurses, managers, and PIs periodically reviewed the data-entry process to prevent persisting data recording errors.
The efficacy data set comprised all participants who had the primary outcome measured in week 5 of at least 1 treatment period. Following the intention-to-treat (ITT) principle, data were analyzed according to the randomized sequence assignment, even if participants received the medications in a different sequence.
The safety data set included all participants who received at least 1 dose of any study medication. Participants were analyzed according to the actual treatment received.
We used a linear mixed-effects regression model in the efficacy data set for the primary outcome measure (total MFIS score) using restricted maximum likelihood fitting and Kenward-Roger degree-of-freedom adjustments. The fixed predictors were study medications (categorical placebo, amantadine, modafinil, methylphenidate), treatment sequence (categorical 1-4), treatment period (categorical 1-4), and the baseline measure of the outcome and study site (categorical Johns Hopkins Multiple Sclerosis Center/UCSF Multiple Sclerosis and Neuroinflammation Center); participants were the random effect. If the adjusted test of treatment differences across the 4 interventions were significant at the α = .05 level, we would make pairwise comparisons between study treatments using estimated contrasts at the α = .05 level. Estimated mean scores, with 95% CIs, were reported for each drug and the placebo. The other efficacy outcomes were analyzed using similar mixed-effects models. The carryover effect was assessed by including an additional predictor of treatment in the previous time period (missing for time period 1) and testing its significance at α = .05.
Approximate normality was assessed by calculating the conditional, studentized residuals and assessing the approximate normality of a histogram; the absence of outliers (as judged by studentized residuals >3 in absolute value); and, if present, the influence of outliers and a plot of studentized residuals vs predicted values.
For each of the following potential effect modifiers (all measured at screening), an analysis was performed to assess heterogeneity of treatment effects (HTE):
The analysis was a repetition of the primary, mixed-models analysis but included the interaction between the effect modifier and the treatment effect. If the P value for interaction was ≤.15, subgroup analyses were conducted within each subgroup defined by the effect modifier.
We had <10% missing data. Furthermore, the use of mixed-models analyses protects against bias resulting from missing data under the assumption of missingness at random. However, if there were significant missing data for any variable (defined as >15%), we would have conducted a sensitivity analysis using multiple imputations.
The frequency of AEs (and moderate and severe AEs) was tabulated by drug. Moderate AEs were defined as events discomforting enough to limit or interfere with daily activities. Severe AEs were defined as events that resulted in significant symptoms that prevented normal daily activities. For tolerability, we reported the proportion of participants who reached the maximum dose and the half-maximum dose as well as the proportion who discontinued the medication; the average and range of the maximum tolerated dose were calculated for each drug. Also, 95% CIs were calculated for each drug.
The changes made to the original study protocol are depicted in Table 3. All the protocol changes were approved by the IRB at participating sites. Changes in the protocol that were made on July 12, 2017, and August 17, 2017, predated the start of recruitment in the study.
Changes Made to the Original Study Protocol.
In total, 169 patients with MS were screened for participation in this clinical trial. Of these, 146 were eligible, and 141 underwent randomization (75 at the Johns Hopkins Multiple Sclerosis Center and 66 at the UCSF Multiple Sclerosis and Neuroinflammation Center). In total, 111 participants completed all 4 medication periods (Figure 3). The demographic and baseline characteristics (at the time of screening) of randomized participants are shown in Table 4. There was no imbalance in the baseline characteristics among the 4 treatment sequences. Only 4 participants reported an MS relapse during the study.
CONSORT Diagram.
Baseline (Screening) Characteristics of Randomized Participants.
In total, 136 participants completed at least 1 medication period and participated in the ITT efficacy analysis. The estimated mean values for the total MFIS score (± SE) at the highest or maximum tolerated dose in each medication period were as follows: 40.6 ± 1.2 with placebo, 41.3 ± 1.2 with amantadine, 39.0 ± 1.2 with modafinil, and 38.6 ± 1.2 with methylphenidate (Table 5 and Figure 4). The primary analysis did not show any significant main effect of treatment (P = .20), treatment sequence (P = .44), treatment period (P = .50), or site (P = .60). In exploratory preplanned pairwise comparisons, estimated means of total MFIS score did not differ between amantadine, modafinil, methylphenidate, and placebo (Table 6).
Mean ± SE Baseline Values and Estimated Mean ± SE for Each Medication Period.
Mean MFIS Score at Baseline and During the Highest Tolerated Dose of Each Medicationa.
Pairwise Comparison of Estimated Means of Total MFIS Score for Each Medication Period.
Table 5 shows the average Neuro-QoL fatigue item bank T and ESS scores at baseline and at the maximum tolerated dose of each study medication period. There was no treatment effect on the average Neuro-QoL fatigue item bank T score (P = .42) or the ESS score (P = .071).
Although no significant treatment effect was found for the physical and cognitive subscales of the MFIS, a significant treatment effect was seen on the psychosocial subscale. On pairwise comparisons, methylphenidate improved the psychosocial subscale of the MFIS compared with placebo (adjusted mean difference 0.5; SE, 0.2; P = .008).
There was no statistically significant difference in the proportion of participants who improved on placebo compared with other study medications. The proportions of participants with at least a 4-point improvement in the total MFIS score compared with their baseline score were as follows: 70% with placebo, 62% with amantadine, 76% with modafinil, and 75% with methylphenidate. The proportions of participants with at least a 10-point improvement in the total MFIS score compared with their baseline score were as follows: 50% with placebo, 45% with amantadine, 54% with modafinil, and 57% with methylphenidate.
In response to the question, “Going forward, would you choose this medication as your fatigue treatment,” which was asked at the end of each medication period, the following proportions answered “yes”: 32% with placebo, 33% with amantadine, 44% with modafinil, and 43% with methylphenidate. We describe this further in the Discussion section.
Sensitivity analyses for carryover effects were conducted by including an additional predictor of treatment in the previous time period in the mixed-effects models. There was no significant carryover effect for the total MFIS scores, Neuro-QoL fatigue item bank values, and ESS models (data not shown).
We evaluated the trial post hoc as a parallel-group design by restricting the primary efficacy outcome analysis to the first medication period. The estimated mean values for the total MFIS score (± SE) at the highest or maximum tolerated dose in the first medication period were as follows: 39.8 ± 2.4 with placebo, 43.4 ± 2.4 with amantadine, 37.2 ± 2.4 with modafinil, and 39.8 ± 2.3 with methylphenidate. In pairwise comparisons, there was no statistically significant difference between study drugs in the estimated mean values of total MFIS score in the first medication period (data not shown).
Relapsing-remitting vs progressive MS, high vs low screening depression scores, taking vs not taking a DMT, and high vs low EDSS score at the time of screening did not modify the effect of treatment on the total MFIS score (ie, there was no HTE based on these prespecified factors). However, in a post hoc analysis, there was an interaction between baseline ESS score and treatment effect on the primary fatigue outcome (P value of the interaction test = .024). More than 50% of participants in the efficacy data set had excessive daytime sleepiness at baseline. Among those (ESS score >10), the estimated means of total MFIS scores for modafinil and methylphenidate were 4.1 points lower than placebo (95% CI, −8.0 to −0.3; P = .034; and 95% CI, −7.9 to −0.2; P = .037, respectively) (Table 7). In participants with no excessive daytime sleepiness at baseline (ESS score ≤10), the estimated means of total MFIS scores for amantadine, modafinil, and methylphenidate were not significantly different from placebo.
Pairwise Comparison of Estimated Means of Total MFIS Score for Each Medication Period in Participants With and Without Excessive Daytime Sleepiness.
In total, 92.1% of participants tolerated the maximum dose of amantadine (200 mg daily), while 86.4% and 86.8% tolerated the maximum doses of modafinil (200 mg daily) and methylphenidate (20 mg daily), respectively. In total, 94.4% of participants tolerated the maximum number of placebo capsules; 5.5% of participants discontinued amantadine before the end of the medication period, and 94.5% tolerated at least half of the maximum dose. In total, 8.0% and 5.4% of participants stopped modafinil and methylphenidate, respectively, before the end of the medication period. In addition, 92% of the participants tolerated at least half of the maximum dose of modafinil. This number was 91.5% for methylphenidate.
The estimated means (95% CI) for the highest tolerated dose of medication were as follows: 186.4 (179.8-192.9) mg/day for amantadine, 178.3 (171.7-184.9) mg/day for modafinil, and 17.5 (16.6-18.4) mg/day for methylphenidate.
AEs are shown in Table 8. In total, 30.6% of participants reported at least 1 AE while taking placebo; 39.2%, 40.0%, and 39.8% of participants reported at least 1 AE while taking amantadine, modafinil, and methylphenidate, respectively. The total numbers of moderate to severe AEs in each medication period were as follows: 28 with amantadine, 31 with modafinil, 40 with methylphenidate, and 18 with placebo. The most striking imbalance in the frequency of AEs was related to those categorized as nervous system disorders or psychiatric disorders, the most common being headaches, insomnia, lightheadedness and dizziness, and anxiety. The most common gastrointestinal AEs were nausea, dry mouth, and constipation. Three serious AEs occurred during the study (pulmonary embolism and myocarditis while taking amantadine, and an MS exacerbation requiring hospitalization while taking modafinil). None of these serious AEs were judged by the PIs to be related to study medications.
Adverse Events.
Our randomized, double-blind, crossover trial showed that amantadine, modafinil, and methylphenidate were not superior to placebo in improving MS-related fatigue as determined with validated outcome measures (MFIS as primary outcome and Neuro-QoL fatigue item bank as secondary outcome). The average MFIS score (on a scale from 0 to 84) improved by almost 10 points on average from baseline in the placebo group, which is comparable to prior trials in MS fatigue.22 Compared with placebo, the MFIS score worsened by 0.6 points on average with amantadine, while it improved marginally with modafinil and methylphenidate (1.6 points and 2.0 points, respectively). These differences were neither statistically nor clinically significant, as a minimum difference of 4 to 8 points has been reported to be clinically meaningful.45 Our trial had 80% power to detect a 4-point difference in total MFIS score between the placebo and each medication. The very small absolute differences between study drugs and placebo (as well as the 95% CIs) argue against inadequate sample size as the underlying reason for this negative trial. Even if the differences had been statistically significant, the small effect size would not be considered clinically relevant to support the clinical use of these drugs. However, modafinil and methylphenidate may have a marginal but clinically significant effect on fatigue severity in patients with excessive daytime sleepiness.
Although methylphenidate had never been tested in an RCT for MS-related fatigue, amantadine and modafinil have been tested in numerous RCTs for this clinical condition.11,23 The results of these trials were mixed: some reported that amantadine and modafinil were effective for MS-related fatigue, whereas others did not report a benefit.13,14,18,20-22,42,51-59
Three randomized, double-blind trials that reported the superiority of amantadine (200 mg/day) over placebo in reducing MS-related fatigue used visual analog scale, daily diary rating, and MS-specific fatigue scales as their outcome measures.18,51,52 However, 1 of these trials reported no effect of amantadine as measured by the FSS, one of the better validated and commonly used fatigue scales in MS.18 Another clinical trial reported a benefit of amantadine 200 mg/day compared with placebo on MFIS score13; however, it was not double blinded, had only 15 participants in each treatment group, and featured a major imbalance in baseline MFIS scores between the 2 groups. A parallel-group, randomized, double-blind, placebo-controlled study reported a statistically significant effect of amantadine 200 mg/day (compared with placebo) on FSS score but had a total sample size of only 42 participants.54
Multiple placebo-controlled, patient-blind, or double-blind RCTs with sample sizes ranging between 21 and 121 participants tested the efficacy of modafinil 200 to 400 mg/day in reducing MFIS or FSS scores.13,22,56,59 All reported that modafinil was not superior to placebo in improving MS-related fatigue. A 72-participant, placebo-controlled trial that reported improvement in MFIS and FSS scores with 200 mg/day of modafinil (but not with 400 mg/day) was a single-blind study.42 Another double-blind RCT of modafinil 200 mg/day vs placebo with 21 participants reported an improvement in FSS score in the modafinil group.21
Although those trials included different populations and used various designs and outcome measures, we speculate that the magnitude of the placebo effect and adequacy of blinding treatment allocation might have contributed greatly to the disparate findings. The large placebo effect has been reported in several clinical trials of fatigue treatment in MS18,22,51 and other medical conditions,60 and the variation in the effects of placebo on an outcome is partly explained by how a trial is conducted.61
Based on previous conflicting trial results, we planned additional safeguards to further explore potentially negative results using several validated MS fatigue scales. For example, our primary outcome, the MFIS, has several dimensions and a 28-day look-back period, while 1 of our secondary outcomes, the Neuro-QoL fatigue item bank, is a more recently developed tool with a 7-day look-back period. There was no medication effect on either outcome measure in our trial.
Fatigue (defined as a subjective lack of physical or mental energy perceived by the individual with usual activities) is distinct from but sometimes associated with excessive daytime sleepiness. The effect of medications on fatigue may be modified by the presence of daytime sleepiness. In our post hoc analysis, modafinil and methylphenidate improved fatigue severity more than placebo in patients with excessive daytime sleepiness. These improvements were marginally clinically significant (a little more than 4 points on total MFIS score). This observation is in line with another clinical trial of modafinil, which reported an improvement in the physical subscale of the MFIS only in patients with excessive daytime sleepiness.22 These results suggest that excessive daytime sleepiness or its underlying pathophysiology may contribute to fatigue severity in a subset of patients with MS. In those patients, wake-promoting agents, such as modafinil and methylphenidate, may have a marginal but clinically significant effect on improving fatigue. These results were obtained from post hoc analyses and should be interpreted with caution.
Although these drugs did not improve fatigue more than placebo, a significantly higher proportion of participants said they would choose modafinil (44.4%) or methylphenidate (43.3%) as their long-term fatigue treatment compared with placebo (32.0%). Although this finding may be related to the benefits of these medications in alleviating MS symptoms other than fatigue, we also cannot exclude the possibility that the MFIS and Neuro-QoL may not completely capture some dimensions of fatigue. The increased proportion of participants who would choose modafinil as their long-term fatigue treatment may, in fact, be related to the marginal improvement in the excessive daytime sleepiness; for those who would choose methylphenidate, it might be related to improved attention, which was not tested in our study.
Most participants could tolerate the maximum dose of all study medications; however, the total numbers of AEs, moderate to severe AEs, and AEs categorized as nervous system or psychiatric disorders, as well as the proportion of participants who reported any AEs, were higher with amantadine, modafinil, and methylphenidate than with placebo. The higher frequency and the profile of AEs associated with these 3 drugs over a short period should be taken into consideration when used for symptom management in patients with MS. It is possible that their long-term use may result in a higher frequency of AEs and lower tolerability. Their side effect profile may also change with increasing duration of exposure.
As a pragmatic trial, this study was designed to mimic the use of commonly prescribed MS fatigue medications in clinical practice. Some clinicians prescribe “fatigue medications” to patients who report having fatigue that is unusual and disruptive, do not have a clear reason for secondary fatigue (such as untreated hypothyroidism, anemia, and sleep apnea), and do not have a clear contraindication for receiving these medications. Demographics, type of MS, level of disability, presence of depression, and taking MS DMTs do not generally affect the decision to prescribe fatigue medications. Our study demonstrated that amantadine, modafinil, and methylphenidate, at doses often used in clinical practice, do not provide additional benefits over placebo in reducing fatigue severity in patients with MS. The effects of these medications were not different in prespecified subgroups (relapsing-remitting vs progressive MS, depressed vs not depressed, taking a DMT vs not, severe disability vs less severe).
Our study has several major strengths. Our eligibility criteria were broad; thus, the results are generalizable. The participants were of diverse racial and ethnic backgrounds and had a wide range of MS-related disability. The recruitment was conducted at 2 MS specialty clinics, with a referral from clinicians and minimal extra effort for recruitment through advertising; thus, the trial setting was not significantly different from usual care for MS. The multiple crossover design of the study helped preserve participant blinding to study medication, although not formally assessed, in addition to testing several drugs by using each participant as his or her own control, increasing power and promoting recruitment. The study outcomes were all validated patient-reported metrics that are directly relevant to participants. After a single in-person screening visit, study outcomes were collected remotely, with minimal disruption to participants' lives. Participants were contacted several times during each medication period and asked about the tolerability and side effects, leading to optimal treatment dose adjustment (a departure from pragmatic trial usual practice). Considering the number of end points collected (N = 498), this is the largest clinical trial of MS fatigue treatment thus far. Finally, the mixed-effects analysis method was robust against missing data, and the sensitivity analyses did not show any carryover effect (ie, the washout periods were adequate in length).
This study also has several limitations. First, it was conducted at only 2 specialty MS clinics; therefore, the results may not be applicable to all patients with MS. Second, duration of participation in the study was relatively long because of the crossover design. If there were large-scale fluctuations in fatigue levels over time, they might have biased the results toward the null (ie, no medication effect). Diurnal and day-to-day fluctuations in fatigue are well-known phenomena in MS,62 but large-scale and long-term fluctuations in fatigue levels are not common,63 and, contrary to popular belief, fatigue severity does not fluctuate between seasons in patients with MS.64 Although MS exacerbations may change fatigue severity, only 4 patients reported relapses during the study. Additionally, when we analyzed the study as a 6-week-long, parallel-group trial by using only the treatment period 1 outcome, the results were not different from the overall findings: no medication was better than placebo in changing fatigue severity. Third, each treatment period was short and used specific doses of medications. Patients were on the maximum doses for just 7 to 14 days at the time of the MFIS assessment in week 5, which meant that the MFIS (with a 28-day look-back) is effectively averaging over that maximum dose as well as the lower doses that the participants received in the first 3 weeks. The results, however, were similar for the Neuro-QoL fatigue item bank, which has a 7-day look-back. We cannot rule out that the results might have been different with long-term use and higher doses of study drugs; however, doses of modafinil and amantadine used in prior trials (200-400 mg/day for modafinil and 200 mg/day for amantadine) are in line with the doses we selected, and higher doses result in an increased incidence of AEs and lower tolerability. Finally, amphetamine-like stimulants other than methylphenidate may have different effects on MS-related fatigue.
Amantadine, modafinil, and methylphenidate were not superior to placebo in improving MS fatigue and resulted in more frequent AEs. Modafinil and methylphenidate may result in a small but clinically significant improvement in fatigue in a subset of patients with excessive daytime sleepiness. Further research on MS fatigue is needed to elucidate its pathophysiology, improve outcome measures, and develop effective interventions.
We are thankful to the patients who participated in this clinical trial. We are grateful to the members of the SAC and for the oversight of the data and safety monitoring board composed of Myla Goldman, MD; Deborah Sellmeyer, MD; and Amber Salter, PhD. We thank the Clinical & Translational Science Institute at UCSF for its technical support.
Research reported in this report was funded through a Patient-Centered Outcomes Research Institute® (PCORI®) Award (MS-1511-33689). Further information available at: https://www.pcori.org/research-results/2016/comparing-medicines-help-patients-multiple-sclerosis-feel-less-fatigued
Nourbakhsh B, Revirajan N, Morris B, et al. (2021). Comparing Medicines to Help Patients with Multiple Sclerosis Feel Less Fatigued—The TRIUMPHANT-MS Study. Patient-Centered Outcomes Research Institute (PCORI). https://doi.org/10.25302/06.2021.MS.151133689
The [views, statements, opinions] presented in this report are solely the responsibility of the author(s) and do not necessarily represent the views of the Patient-Centered Outcomes Research Institute® (PCORI®), its Board of Governors or Methodology Committee.
This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License which permits noncommercial use and distribution provided the original author(s) and source are credited. (See https://creativecommons.org/licenses/by-nc-nd/4.0/
Your browsing activity is empty.
Activity recording is turned off.
See more...
