Updated PCORI Evidence Map: Treatments for Fatigue in Multiple Sclerosis

Prepared by

ECRI Institute‐Penn Medicine Evidence‐based Practice Center 5200 Butler Pike Plymouth Meeting, PA 19462

Contributors:

Jonathan R. Treadwell, Ph.D., ECRI Institute Amy Tsou, M.D., M.Sc. ECRI Institute Eileen Erinoff, M.S.L.I.S., ECRI Institute Karen Schoelles, M.D., S.M., ECRI Institute

Submitted September 2018 i

Contents Background ...... 1 Methods ...... 3 Literature Search ...... 3 Inclusion Criteria ...... 3 Risk of Bias Assessment ...... 3 Data Extraction and Meta‐Analysis ...... 4 Instruments for Measuring Fatigue ...... 4 Minimum Important Difference (MID) ...... 5 Strength of Evidence Ratings ...... 5 Map Construction ...... 6 Results ...... 6 Evidence Base ...... 6 Summary of the Abstracts in Evidence Map 1 (all study designs) ...... 9 Summary of the Trials in Evidence Map 2 (active vs. inactive treatments) ...... 13 Summary of the Trials in Evidence Map 3 (active vs. active treatments) ...... 18 Limitations ...... 21 Future Research ...... 23 References ...... 25 Appendices ...... 47 Appendix A. Literature Search Methods ...... 47 Appendix B. Included and Excluded Interventions ...... 52 Appendix C. Related PCORI‐funded Projects and clinicaltrials.gov records ...... 54 Appendix D. Evidence Tables ...... 64 Appendix E. September 2018 Map Updates ...... 96 Figures Figure 1. Article Flow ...... 8 Figure 2. Screenshot for Evidence Map 1 (overview) ...... 12 Figure 3. Screenshot for the Exercise section of Evidence Map 2 (comparisons to inactive treatment) .... 15 Figure 4. Screenshot for Evidence Map 3 (comparisons between active treatments) ...... 20

Tables

Table 1. Overview of Interventions and Study Designs in Evidence Map 1 ...... 10 Table 2. Treatments with Sufficient Evidence of Impact on Fatigue ...... 18 Table 3. Related PCORI‐funded Projects ...... 54 Table 4. Related Records in clinicaltrials.gov ...... 55 Table 5. Data for Evidence Map 1 (Abstracts on Interventions for Fatigue in MS) ...... 64 Table 6. Fatigue And Quality of Life Data for Evidence Map 2: Pharmacologic Interventions ...... 77 Table 7. Fatigue And Quality of Life Data for Evidence Map 2: Exercise Interventions ...... 78 Table 8. Fatigue and Quality of Life Data for Evidence Map 2: Behavioral/Educational Interventions83 Table 9. Fatigue And Quality of Life Data for Evidence Map 2: Complementary and Alternative Medicine (CAM) Interventions ...... 89 Table 10. Fatigue And Quality of Life Data for Evidence Map 2: Other Interventions ...... 90 Table 11. Adverse Effects Data for Evidence Map 2 ...... 91 Table 12. Fatigue Data for Evidence Map 3 ...... 94

Background Multiple sclerosis (MS) is the most common disabling neurological disease in young adults, estimated to affect 250,000 to 350,000 Americans.1 While MS can cause many types of disability, fatigue is the most frequently reported symptom, affecting 50 to 80% of patients.2,3 Fatigue is more prevalent in progressive MS compared to relapsing remitting multiple sclerosis (RRMS), and may arise from the disease itself, or from secondary causes such as disease‐modifying drugs (i.e., interferon‐beta), medication side effects (e.g., baclofen), mood, sleep disorders, or environmental factors (i.e., heat, humidity).3 Notably, many patients report fatigue to be the most troubling symptom.2,4,5 A broad range of interventions exist, including various drugs, exercise, cognitive behavioral therapy, self‐management strategies, and non‐invasive brain stimulation.6 However, important questions remain regarding efficacy, due in part, to several methodologic issues. First, clinical progression is highly heterogeneous: on average patients with RRMS have 0.4 to 0.6 relapses per year, with minimal progression between relapses;7 in contrast, patients with primary or secondary progressive MS experience continuous gradual worsening. Even within each subtype, the rate of progression varies; furthermore, studies often enroll patients with both RRMS and progressive MS patterns, without providing separate analysis.3 A second problem is absence of consensus regarding the definition and measurement of fatigue.2,6,8 Patients, caregivers and researchers may variably consider fatigue as tiredness, decreased motivation, or physical weakness subsequent to muscle activation.6 Also, key differences exist between the two most common measures of fatigue, the Fatigue Severity Scale (FSS) and the Modified Fatigue Impact Scale (MFIS).6 The FSS focuses on physical fatigue and its influence on daily function, while in contrast, the MFIS captures cognitive, physical, and psychosocial components of fatigue. Furthermore, some items in the FSS assess the quality of fatigue instead of severity. Thus, while both scales have good validity and reliability, only a moderate correlation between the two has been found, a problematic fact for interpreting studies using these different measures.6 Data on practice patterns in the United States is scarce. However, a typical approach involves initially addressing potential secondary causes of fatigue such as depression or side effects from disease‐ modifying drugs. If fatigue persists, common treatment strategies include drugs such as amantadine, dalfampridine, and stimulants (including modafinil, armodafinil, detroamphetamine‐amphetamine, and methylphenidate). Non‐pharmacologic strategies considered include exercise programs (such as physical therapy), cooling therapies, and fatigue management programs. A 2014 American Academy of Neurology (AAN) guideline noted that magnetic therapy was “probably effective” for fatigue reduction, but use appears rare.9 Similarly, although a 2014 United Kingdom guideline recommended clinicians consider mindfulness based training, cognitive behavioral therapy, and yoga, it is unclear if these interventions are routinely offered to patients in the United States.10 In this project, we systematically identified relevant research studies of fatigue interventions in MS, extracted data, performed meta‐analyses, and rated the strength of evidence. We then organized information into three Web‐based, interactive evidence maps to aid decision‐making for patients, 1

clinicians, researchers, and policy‐makers. This document describes the updated maps (September 2018), and Appendix E lists all changes since the original maps (February 2018).

Methods Literature Search An experienced information specialist performed all searches for this project. Our comprehensive search protocol included the PubMed, EMBASE/Medline, and PsycINFO databases, limited to publications from 1987 onward. We also searched the National Guideline Clearinghouse to identify clinical practice guidelines that addressed this topic. We present the strategies in Embase.com syntax (using EMTREE) in Appendix A. We translated controlled vocabulary terms and syntax for the PubMed and PsycINFO searches. To identify additional trials in this topic area, we searched ClinicalTrials.gov and the PCORI Web site. Inclusion Criteria Our study inclusion criteria were informed by discussions with a clinical expert. For Map 1, we set the following inclusion criteria:  English language abstract  Enrolled at least 10 patients  Empirical study  MS patients (any type)  Adults (age ≥18)  Used at least one treatment of interest (see a list of included and excluded interventions in Appendix B)  Primary study publication  One of the possible results of the treatment was reduced fatigue (although abstracts were not required to state this)  For case series, results for fatigue were reported in the abstract

We set the following inclusion criteria for Maps 2 and 3:  Met all of above criteria for Map 1  Full article in English  Random assignment to treatments  The comparator treatment was either an inactive treatment (Map 2) or another active treatment of interest (Map 3)  Reported outcome data at least eight weeks after the start of treatment  Reported comparative data on either fatigue or quality of life (or both)  At least 15 patients in each group at follow‐up Risk of Bias Assessment For randomized trials included for Maps 2 and 3, we rated risk of bias as Low, Moderate, or High. We considered various aspects of study design and conduct such as method of randomization, concealment of allocation, baseline group similarity, intention‐to‐treat analysis, blinding of patients/physicians/outcome assessors, and rate of incomplete data.

Data Extraction and Meta‐Analysis We extracted data for Map 1 from a review of abstracts only. We extracted treatment category (or categories if the study used multiple treatments of interest), the specific treatment, the enrolled number of patients (N), year of publication, and whether the studies were U.S./non‐U.S./unknown. For Maps 2 and 3, we obtained full‐text articles and extracted all of the above; in addition, we extracted length of follow‐up, number of patients contributing data at follow‐up, instruments used to measure fatigue and quality of life, and outcome data (fatigue, quality of life, adverse effects). For fatigue and quality of life, we extracted baseline and follow‐up data (means and standard deviations, typically) for all relevant treatment groups. If the study reported multiple follow‐up time‐points, we extracted only the longest. For fatigue, we extracted any reported 8‐week or later data on the Fatigue Severity Scale (FSS) and the Modified Fatigue Impact Scale (MFIS). If neither of these were reported, we extracted data on other reported fatigue scales. For quality of life, we extracted any reported 8‐week or later data on the Short Form 36 (SF‐36) and the Multiple Sclerosis Impact Scale 29 (MSIS‐29); if neither of these were reported, we extracted data on other reported quality of life scales. For crossover trials, we only extracted the period 1 data (to avoid carryover effects). Where possible, we extracted enough information to estimate Hedges’ g (a form of standardized mean difference) and its standard error. We examined all treatment comparisons to determine which comparisons were similar enough to combine in meta‐analyses. Then we performed random‐effects meta‐analysis of Hedges’ g using the method of DerSimonian and Laird.11 To incorporate the baseline data (where reported), we assumed a pre‐post correlation of 0.5.12 Meta‐analysis was performed using Comprehensive Meta‐Analysis version 2.2.048. We converted each Hedges’ g to the original scales by multiplying by the pooled standard deviation of the scale of interest. Instruments for Measuring Fatigue The two most common instruments to measure fatigue in MS are the Fatigue Severity Scale (FSS) and the Modified Fatigue Impact Scale (MFIS). This section provides information on these instruments including the types of questions, instrument length, and the scale ranges. Fatigue Severity Scale (FSS) The FSS contains nine statements, each one involving fatigue (e.g., “My motivation is lower when I am fatigued”). Patients rate their agreement from 1–7, where 1 indicates “Strongly disagree” and 7 indicates “Strongly agree”. Therefore, higher scores indicate greater fatigue. Some studies report the total score (ranging from 9–63); other studies report average score (ranging from 1–7). The standard deviation (SD) of FSS scores (1–7 scale) in the studies for maps 2–3 ranged from 0.65 to 3.1, and the median SD was 1.3. Modified Fatigue Impact Scale (MFIS) The MFIS contains 21 statements, each one involving fatigue (e.g., “I have been less alert”) during the last 4 weeks. Patients rate agreement from 0 to 4 where 0 indicates “Never” and 4 indicates “Almost Always.” Therefore, as with the FSS, higher scores indicate greater fatigue. Studies reported the total

score, which ranges from 0–84.The SD of MFIS scores in the studies for Maps 2‐3 ranged from 8–23, and the median SD was 14.6. Therefore, an MID of 20.2 points corresponds to a Hedges’ g of 20.2/14.6, or g=1.38. Minimum Important Difference (MID) Interpreting improvements on quantitative scales (such as the FSS and the MFIS) can be difficult. Ideally, numerical changes would translate to specific abilities in the day‐to‐day life of patients. Unfortunately, we identified no such translations in the literature. However, we did identify some literature on the minimum important difference (MID). According to Zhang et al. (2015),13 the MID is the “smallest difference in score in the outcome of interest that informed patients or proxies perceive as important, either beneficial or harmful, and leads the patient or clinician to consider a change in the management.”13 For the FSS, we identified two estimates of the MID:  Learmonth et al. (2013)14 used a distribution‐based method and found that for the FSS, the MID is 1.9 points on the 1–7 scale. This corresponds to a Hedges’ g of 1.9/1.3, or g=1.46.  Robinson et al. (2009)15 used a clinical anchor‐based method and found that for the FSS, the MID is 1 point on the 1‐7 scale. This corresponds to a Hedges’ g of 1/1.3, or g=0.77.

The discrepancy in MID estimates for the FSS (0.9 points) is notable given that the scale range is only six points wide. The difference may be due to their differing methods. Some have argued that a clinical anchor‐based method is preferable.13 Thus, one might consider prioritizing the estimate from Robinson et al. (2009)15 (1‐point change). However, Robinson et al. (2009)15 included only patients with RRMS (who were required to have had recent relapses for inclusion). Ultimately, only a minority of randomized trials we included for this project focused on RRMS patients alone. Thus, the generalizability of the MID reported by Robinson et al. (2009)15 is limited. For the MFIS, we identified only one study describing an MID; Learmonth et al (2013)14 estimated an MID to be 20.2 (on a scale of 0 to 84). More work is needed to determine an accurate estimate of MID and account for potential differences among various MS subtypes. For this reason, we chose not to incorporate MIDs into the evidence maps. However, in the text below, we note any interventions that met either or both of the MID thresholds for the FSS. Strength of Evidence Ratings For fatigue and quality of life outcomes, we rated the strength of evidence for each comparison as High, Moderate, Low, or Insufficient. This categorization corresponds to the EPC system,16 which is similar to GRADE. The lowest rating (Insufficient) indicates that no conclusion can be drawn from the evidence, whereas the other ratings indicate varying levels of confidence. For a given comparison, we started the rating at High, as only RCTs were included. We then considered four domains to rate the strength of evidence:

 Risk of bias (see earlier section for details). Studies rated at Low risk of bias received no downgrade, moderate risk of bias received a single downgrade, and high risk of bias received a double downgrade.  Directness. Our inclusion criteria required that studies enroll adult MS patients who received interventions and reported patient‐oriented outcomes of fatigue or quality of life. Therefore, we did not downgrade for indirectness.  Consistency. When multiple studies of the same comparison reported on the same outcome, we determined subjectively whether to downgrade for inconsistent results between studies. This could have been either a single or a double downgrade. For a single‐study evidence base, we applied a single downgrade due to the lack of replication of findings.  Precision. We rated precision by considering first whether the evidence was precise enough to permit a conclusion. A statistically significant difference is sufficiently precise. A statistically non‐ significant difference is sufficiently precise if the confidence interval around the nonsignificant finding is within +/‐0.2 of zero (i.e., precise enough to conclude approximate equivalence). With wider confidence intervals, we deemed nonsignificant findings inconclusive, since the data do not rule out an important effect. We used a threshold of 0.2 for this decision based on the recommendation by Cohen et al. (1988)17 that 0.2 is considered a small effect size.

Inconclusive findings, and other any findings with serious problems with risk of bias and/or consistency, were rated as Insufficient. All other findings were rated as High, Moderate, or Low depending on the domains listed above. Map Construction Experienced Web programmers constructed all maps using HTML, SVG and JavaScript. Based on suggestions from the content team, they made iterative improvements to optimize usability and informativeness. Graphic designers informed design of colors and layout.

Results Evidence Base Our searches yielded 1,718 potentially relevant articles (see article flow in Figure 1 below). Abstract screening resulted in the exclusion of 1,436 articles from all evidence maps. The three most common exclusions were due to 1) articles not testing any specific intervention, 2) articles being reviews or commentaries (instead of research studies), and 3) articles describing interventions not intended to treat fatigue, such as disease‐modifying drugs. The remaining 282 abstracts were included in Evidence Map 1. Of those, we examined the full text of the 178 randomized trials for possible inclusion in Evidence Maps 2 or 3. This resulted in the exclusion of 122 randomized trials. The most frequent reasons for exclusion were followup less than 8 weeks, not a full‐length article (i.e., only an abstract), and number of patients per treatment group of less than 15 at follow‐up. Thus, we included 56 randomized trials for Evidence Maps 2 and 3 (45 for Map 2 18‐62 and 15 for Map 3; 63‐73 four trials were included for both).59‐62 In addition, we identified six pertinent PCORI‐ funded trials and 29 pertinent records in clinicaltrials.gov (see details in Appendix C).74‐78

Prior to treatment, MS patients in the 56 trials had considerable fatigue severity with a strong impact on their lives. Among 41 treatment groups in trials reporting the FSS, the median FSS score was 4.9 on the 1–7 scale (25th percentile of 4.4, and 75th percentile of 5.6). Regarding the impact of fatigue as measured by the MFIS, among 39 treatment groups in studies reporting the MFIS, the median MFIS score was 43 on the 0–84 scale (25th percentile of 36, and 75th percentile of 47). Regarding MS type, 73% of the 56 trials had mixed types or did not report MS types. The remaining 27% focused on RRMS. Studies’ longest followup timepoint (the amount of time between the start of treatment and the measurement of outcome) was 8–12 weeks for 43% of the studies, 13–24 weeks for another 20%, and 25 weeks or more for the remaining 38%.

Figure 1. Article Flow

1,718 publications identified

Abstracts screened 1,436 excluded from all maps

EVIDENCE MAP 1: 282 abstracts: - 74 case series - 30 nonrandomized controlled studies - 178 randomized trials

122 randomized trials excluded: 50: <8 weeks follow-up 34: Follow-up Ns <15 per group Full text review 30: Just an abstract of 178 randomized 4: Only compared active treatments, and only one was of interest trials 2: Did not report results for fatigue, quality of life or adverse effects 1: Did not report comparative post-treatment data 1: Did not report comparative data past 8 weeks

56 randomized trials included for either Map 2 or Map 3 or both*

EVIDENCE MAP 2: EVIDENCE MAP 3: 45 randomized trials 15 randomized trials Active vs. inactive Active vs. active

* 4 randomized trials had 3+ groups and were included in both Map 2 and Map 3

Summary of the Abstracts in Evidence Map 1 (all study designs) The 282 included abstracts reported 361 groups of MS patients receiving an intervention of interest (see Table 5 in Appendix D). We included 178 randomized trials, 30 nonrandomized studies comparing treatments, and 74 case series. Studies were mostly recent, with 26% appearing in 2016 or 2017, 51% in 2011–2015, 12% in 2006–2010, 9% in 2001–2005, and 3% in 2000 or earlier. A majority (roughly 71%) were performed in countries outside the United States; 20% were performed in the United States, and for 9% the country was unclear from the abstract and database record. Table 1 (below) summarizes studies identified by treatment category for Map 1, and number of RCTs for each intervention type. Of note, studies comparing more than one intervention are included in counts for each intervention. As several studies compared multiple interventions (often from more than one category), the number of RCTs sums to more than the total RCTs listed for each category.

Table 1. Overview of Interventions and Study Designs in Evidence Map 1 Number of Randomized Number of Interventions Controlled Interventions RCTs Trials (RCTs) Pharmacologic (57 studies): RCTs: 31, Controlled Trials: 5, Case Series: 21  3, 4 diaminopyridine 1  histamine 0  4’aminopyridine 10  histamine + caffeine 0  amantadine 8  L-carnitine 3  amantadine + aspirin 1  methylphenidate 1  armodafinil 1  modafinil 6  aspirin 4  paroxetine 1  citalopram 0  sertraline 1  duloxetine 0  venlafaxine 0  fluoxetine 1 Behavioral/Education (76 studies): RCTs: 48, Controlled trials: 5, Case Series: 23  cognitive behavioral therapy 6  occupational therapy (OT) 1 (CBT)  cognitive training 9  Orem’s self-care model 2  education (general) 3  peer support 1  education (on exercise) 6  psychotherapy 1  energy conservation program 3  relaxation 4  Fatigue: Applying Cognitive behavioural and Energy  relaxation + psychological 1 1 effectiveness Techniques to training lifeStyle (FACETS) program  fatigue management program 4  self-management program 8  mindfulness 4  wellness program 1 Exercise (119 studies): RCTs: 78, Controlled trials: 15, Case Series: 26  aerobic exercise 10  physical therapy 7  aquatic exercise 5  pilates 4  balance training 5  rehabilitation 9  endurance exercise 5  resistance training 9  exercise (including exercise  strength training 1 10 programs)  exercise (other) 13  vestibular rehabilitation 2  exercise (supervised) 7  yoga 7  gait training (robot-assisted) 5 Complementary and Alternative Medicine (18 studies): RCTs: 15, Controlled trials: 1, Case Series: 2  lofepramine, L-phenylalanine,  magnetic field therapy 1 6 B-12  cannabis 1  omega 3 1  cooling therapy 4  tetrahydrocannabinol- 1  low fat diet + omega 3 Cannabidiol (THC-CBD) 1 supplementation oromucosal spray

Number of Randomized Number of Interventions Controlled Interventions RCTs Trials (RCTs) Combination (6 studies): RCTs: 2, Controlled Trials: 1, Case Series: 3  exercise, relaxation 1  rehabilitation, repetitive transcranial magnetic 1 stimulation (rTMS) Other (15 studies): RCTs: 11, Controlled Trials: 2, Case Series: 2  rTMS 4  transcranial direct current 7 stimulation (tDCS) Note: For interventions with 0 listed RCTs, we included at least one non‐RCT

For evidence Map 1 (see a screenshot in Figure 2 below), interventions are categorized by overall treatment type and study design (randomized trial, nonrandomized study comparing treatments, or case series). The height of each bubble (y‐axis) corresponds to the number of studies investigating that treatment type; bubble size represents the total number of patients enrolled in studies of that treatment type (including patients receiving inactive treatments such as placebo, sham, waiting list, and passive education). Filters allow selective display by study design, trial location, and year. For RCTs, the small bubbles included within large bubbles show the counts for specific treatments within a category.

Figure 2. Screenshot for Evidence Map 1 (overview)

Examining the map reveals several insights:  Overall, research has focused on exercise (119 studies), behavioral/education (76 studies), and pharmacologic interventions (57 studies), with particular increased attention on exercise and behavioral/education intervention studies in recent years (since 2001).  We found a high proportion of randomized trials. In most areas of medicine, randomized trials are less frequent than case series and nonrandomized controlled trials. By contrast, for interventions for fatigue in MS, randomized trials were the most frequent study design for all categories except combination treatment. This was most striking for exercise interventions, where we included 78 randomized trials that examined an exercise intervention, but only 41 studies with other designs. We required case series (but not other study designs) to report fatigue results in the abstract for inclusion. This may have reduced the number of case series included, and contributed to the relatively high proportion of RCTs.  U.S. studies were relatively more likely to include a pharmacological intervention, but less likely to include an exercise intervention. About 28% of studies including a pharmacological intervention arm were conducted in the United States, whereas only 16% of studies including an exercise were conducted in the United States. Further, 35% of randomized trials of pharmacological agents were conducted in the United States.  We noticed a relative change in the types of treatments under investigation over time. Studies of exercise and behavioral/educational interventions have increased since 2011 (exercise: from 38% of treatment groups before 2011, to 48% of since 2011; behavioral/education: from 20% to 26% of treatment groups). By contrast, studies of pharmacologic and CAM interventions have decreased (pharmacological: from 28% to 15% of all treatment arms; CAM: from 13% to 2% of all treatment arms). Combination and “other” treatment trials have appeared since 2011. Summary of the Trials in Evidence Map 2 (active vs. inactive treatments) We included 45 randomized trials for Evidence Map 2 (see Table 6 through Table 11 in Appendix D). In this map (see Figure 3 for a screenshot) each intervention’s effect on fatigue and quality of life is displayed. When multiple studies reported a given outcome, results were synthesized using meta‐ analysis. Beneficial interventions are shown as green bubbles; outcomes with insufficient evidence are shown in yellow. Furthermore, each bubble’s size corresponds to the magnitude of benefit (Hedges’ g). For trials capturing fatigue using the Modified Fatigue Impact Scale (MFIS) or the Fatigue Severity Scale (FSS), the estimated impact of the intervention may be viewed by hovering over each bubble. When studies reported both MFIS and FSS, we used MFIS to calculate overall effect size. When no bubble appears in a given location (e.g., for example, amantadine has no quality‐of‐life bubble), this indicates that none of the studies reported that outcome. Bubbles with a blue border include PCORI‐funded trials of the intervention. Black dashed circles indicate other ongoing trials listed in ClinicalTrials.gov. The potential for adverse events is represented by small, medium or large red bubbles, reflecting our evidence‐based judgment of the risk and severity of reported adverse effects. Studies explicitly stating that no adverse effects occurred were represented by a small red bubble. When studies failed to report any information on adverse effects, no bubble appears in the adverse effects column. Regarding 13

adverse events, 28 of the 45 trial publications did not mention adverse events, four said only that no adverse events occurred, and the other 13 reported some adverse events (see Table 11 in Appendix D). Filters allow selective display of interventions and efficacy by type of multiple sclerosis, fatigue measurement instrument, and length of follow‐up. Additional details are available when hovering over each bubble, such as assessments of strength of evidence (High/Moderate/Low/Insufficient), number of trials, adverse effects information, and hyperlinks to pertinent abstracts for each bubble.

Figure 3. Screenshot for the Exercise section of Evidence Map 2 (comparisons to inactive treatment)

Examining the full map reveals several insights:  For pharmacologic agents, only paroxetine demonstrated sufficient evidence of efficacy for treating fatigue. Furthermore, no drugs demonstrated efficacy for quality of life, and all were associated with some adverse effects. Insufficient evidence for commonly used medications (amantadine) and lack of evidence for stimulants (such as modafinil, methylphenidate) is striking, given their common use in clinical practice. Thus, forthcoming PCORI‐funded trials assessing amantadine, methyphenidate, and modafinil will address a crucial evidence gap.  For exercise interventions, four interventions demonstrated sufficient evidence of efficacy for both fatigue and quality of life: aquatic exercise, supervised aerobic exercise, unsupervised aerobic exercise, and combination exercises. Yoga improved fatigue, but the strength of existing evidence was insufficient regarding improvements in quality of life. Many studies captured fatigue using the FSS, and exercise interventions typically were associated with 0.7 to 1.7 points of improvement (on the 1‐7 scale).  For behavioral/educational interventions, only fatigue management programs demonstrated sufficient evidence of efficacy for both fatigue and quality of life. Three other specific interventions (i.e., education about physical activity, relaxation training, Fatigue: Applying Cognitive behavioural and Energy effectiveness Techniques to lifeStyle [FACETS] program) improved fatigue, but had insufficient evidence on quality of life. Conversely, mindfulness therapy improved quality of life, but evidence was insufficient for fatigue. PCORI‐funded trials are forthcoming for fatigue management programs and cognitive behavioral therapy.  Only one CAM intervention (lofepramine/L‐phenylalanine) demonstrated sufficient evidence of efficacy for fatigue.

Ten interventions had sufficient evidence of improving fatigue (Table 2 below). The interventions are ordered by the amount of estimated improvement, with the highest‐impact interventions listed first. Note that four of the top five most impactful interventions involved exercise. Only one intervention, aquatic exercise, met the Learmonth threshold (1.9 points) for the MID. Three other interventions (paroxetine, combination exercises, and yoga) met the Robinson threshold (1 point) for the MID but not the Learmonth threshold. The table also translates each Hedges’ g effect size metric into the more easily understood metrics of on the FSS 1‐7 scale and the MFIS 0‐84 scale. These “points” represent estimated improvements from baseline as a result of the intervention. For example, yoga is estimated to improve FSS scores by 1.03 points on average (e.g., from 4.9 at baseline to 3.9 at follow‐up), and MFIS scores by 12 points on average (e.g., from 43 at baseline to 31 at follow‐up). We also list the estimated Hedges’ g impacts on quality of life (QOL) for the ones with sufficient evidence.

Table 2. Treatments with Sufficient Evidence of Impact on Fatigue Translated to Translated to the Impact on Intervention Impact on Fatigue the FSS 1-7 MFIS 0-84 Scale Quality of Life Scale g=1.66 g=1.47 (based on Exercise: Aquatic exercise 2.16 points 24 points (based on 1 RCT25) 3 RCTs25,42,61) Strength: Low Strength: Moderate g=0.84 Pharmacologic: Paroxetine (based on 1 RCT22) 1.1 points 12 points Inconclusive Strength: Low g=0.83 g=0.66 Exercise: Combination (based on 1 RCT45) 1.08 points 12 points (based on 1 RCT45) exercises Strength: Low Strength: Low g=0.79 (based on Exercise: Yoga 1.03 points 12 points Inconclusive 4 RCTs59-62) Strength: Moderate g=0.72 g=0.3 Exercise: Supervised aerobic (based on (based on 0.94 points 11 points exercise 3 RCTs27,60,62) 3 RCTs27,60,62) Strength: Moderate Strength: Moderate g=0.67 Behavioral/Education: (based on 0.87 points 10 points Inconclusive Relaxation training 2 RCTs57,58) Strength: Low g=0.59 Behavioral/Education: (based on 0.77 points 9 points Inconclusive Education on physical activity 3 RCTs28,48,56) Strength: Moderate Behavioral/Education: Fatigue: Applying Cognitive g=0.43 behavioural and Energy (based on 1 RCT49) 0.56 points 6 points Inconclusive effectiveness Techniques to Strength: Moderate lifeStyle (FACETS) program g=0.36 CAM: Lofepramine and (based on 1 RCT20) 0.47 points 5 points Inconclusive L-phenylalanine Strength: Moderate g=0.33 g=0.26 Behavioral/Education: (based on (based on Fatigue management 0.43 points 5 points 5 RCTs23,30,34,35,37) 3 RCTs30,34,37) program Strength: Moderate Strength: Moderate FSS – Fatigue Severity Scale, which ranges from 1–7 where higher numbers represent greater fatigue. Learmonth et al. (2013)14 estimated that the MID is 1.9 points, whereas Robinson et al. (2009)15 estimated it at 1 point. g – Hedges’ g, which is a standardized effect size. Hedges’ g is an N‐corrected form of the standardized mean difference (SMD), which itself is the difference between groups divided by the pooled standard deviation. MFIS – Modified Fatigue Impact Scale, which ranges from 0–84 where higher numbers represent greater fatigue. Learmonth et al. (2013)14 estimated that the MID is 20.2 points. RCTs — Randomized controlled trials Summary of the Trials in Evidence Map 3 (active vs. active treatments) We included 15 randomized trials for Evidence Map 3 (see Table 12 in Appendix D). In this map (see a screenshot in Figure 4 below), dark red bubbles indicate one treatment had a greater impact on fatigue compared to the other (hovering over the bubble displays which intervention was favored).

Yellow bubbles represent comparisons for which there was insufficient evidence. The bubble size corresponds to the size of the difference between treatments (Hedges’ g). Blue bubbles represent ongoing PCORI‐funded studies (for which results are pending). The black dashed circle indicates an ongoing trial listed in ClinicalTrials.gov. Hovering over each bubble provides additional information: which intervention was favored; strength of corresponding evidence (High/Moderate/Low/Insufficient), number of trials, fatigue instrument, multiple sclerosis (MS) type, length of follow‐up, and hyperlinks to abstracts for the relevant studies.

Figure 4. Screenshot for Evidence Map 3 (comparisons between active treatments)

Examining the map reveals several insights:  Most active‐treatment comparisons have only been addressed by single studies. The exception was walking versus yoga (2 studies).  Most comparisons have assessed interventions within the same category (e.g., comparing 2 medications) rather than across categories (e.g., comparing a medication to a behavioral intervention). This is evident in the map because most bubbles fall near the main diagonal.  For most comparisons, the data were inconclusive (due to wide confidence intervals). Studies were generally small, and often MS patients’ fatigue levels improved for both active comparators.  PCORI‐funded trials are examining several novel comparisons, including modafinil versus CBT, the effect of adding CBT to modafinil, amantadine versus modafinil or methylphenidate, and teleconference versus face‐to‐face self‐management programs. Two specific exercise interventions, physical therapy and yoga, have each been assessed by three trials, but not by any PCORI‐funded trials.  Records in clinicaltrials.gov indicate eight more active‐treatment comparisons

Limitations We acknowledge several important limitations to this work. First, Map 1 was based on review of abstracts only (not full text). In some cases, abstracts were unclear and we made an educated guess regarding study design or type of intervention. In reviewing full‐length articles for inclusion in Map 2 or 3, we sometimes discovered that information from abstracts was misleading with regard to study design; in several cases, studies turned out to be secondary publications of an already included study. Given the project timeframe, review of full text for Map 1 was not feasible; however, using abstracts may have led to some inaccuracies. Second, as case series are the least rigorous study design included in Map 1, we excluded all case series abstracts that did not explicitly report fatigue outcomes. However, we did not require abstracts from controlled trials or RCTs to include fatigue outcome results for inclusion. Thus, the relative proportions of 3 study designs in Map 1 (RCTs, controlled trials, case series) may not be completely accurate; specifically, we may have underestimated the number of case series. Third, these maps do not include all existing interventions for fatigue. To promote usability, we prioritized inclusion of interventions commonly used in the United States, while limiting uncommon interventions (e.g., bee venom). For feasibility reasons, with the exception of SSRIs for depression, we did not include interventions aimed at treating secondary causes of fatigue (such as treatment for sleep apnea). Similarly, we considered studies of disease‐modifying therapies to be outside the scope of this project. Although these decisions were informed by discussions with a clinical expert and review of guidelines and narrative reviews, it is possible some patients or clinicians may feel additional interventions should have been included. To decide whether RCTs belonged in Map 2 or 3, we categorized trials as either comparing an intervention to 1) placebo/inactive control or 2) another intervention (i.e., a head‐to‐head trial). For some RCTs included in Map 2, control groups received semi‐active interventions such as monthly phone calls from a neurologist, education through nurse consultations, or “self‐directed” education. We judged

their potential influence on patient outcomes to be sufficiently small enough to be categorized as “inactive.” However, RCTs comparing an active intervention to a semi‐inactive control group could potentially find less pronounced efficacy (compared to studies using inactive control groups (placebo, sham, waitlist). Table 6 through Table 11 in Appendix D list all treatments compared and included in Evidence Map 2 to allow readers to judge for themselves. Another limitation for Map 2 concerns our decision to meta‐analyze some treatments that others might consider too different to combine. For example, we meta‐analyzed three studies18,40,59 that compared some form of aerobic exercise to no intervention. This meta‐analysis assumed, therefore, that the specific type of aerobic exercise does not matter. The data on adverse effects (Map 2) was greatly influenced by what authors chose to report. Most pharmacological studies reported adverse effect (AE) data (red bubbles in Map 2), but non‐ pharmacologic studies typically did not mention whether any patients had experienced AE’s (blank spots in the AE column in Map 2), and a few non‐pharmacological studies stated that no AEs had occurred (small red bubbles in Map 2). In Map 2, studies explicitly reporting no adverse effects are represented with a small red bubble, while this space appears blank for studies that failed to offer any description of adverse effects. Thus, Map 2 may inadvertently suggest that interventions for which authors reported “no adverse effects” have a less favorable benefit‐to‐harm ratio (compared to interventions for which no information on adverse effects was reported). Regarding strength of evidence, for this project, we did not have time to consider the impact of reporting bias. Both the EPC system (which we used for this report) and the GRADE system (a commonly used system) recommend downgrading evidence when there is suspicion of either publication bias or selective outcome reporting.

Future Research Overall, only 10 interventions demonstrated efficacy for treating MS fatigue. The absence of sufficient evidence for pharmacologic treatments such as amantadine, modafinil, and methylphenidate was striking given their common use in clinical practice, and potential for adverse effects (captured in Map 2). Thus, the PCORI funded trial comparing these three drugs to each other and placebo fills a crucial evidence gap. Our findings suggest increased focus on exercise and behavioral/educational interventions is warranted. Based on three RCTs, aquatic exercise not only produced meaningful reductions in fatigue, but improved quality of life. However, these trials were all performed in Iran in predominantly younger women, and may not be broadly generalizable to the U.S. context. Thus, replicating these trials in American patients is important to confirm these findings and further elucidate if particular subgroups may benefit more. Similarly, head‐to‐head comparisons with frequently used treatments (e.g., amantadine) could establish its comparative efficacy. Furthermore, more research should be conducted to clarify the MID for different outcome scales (e.g., FSS, MFIS, and other fatigue scales). This is crucial to allow users of research (such as patients, clinicians, policy makers) to assess if observed effects are large enough to matter in the day‐to‐day lives of patients. Given the varied clinical manifestations and spectrum of disease severity in MS, it would be helpful to have evidence on intervention effects in particular disease subtypes. Most studies enrolled a mix of MS type, yet no studies reported data for separate subgroups (MS type or by disease severity). It is possible that patients with secondary progressive MS respond differently compared patients with other types. Map 1 demonstrates that pharmacologic, behavioral/education, and exercise interventions dominate the research landscape. However, few studies compared interventions across categories (i.e., drug vs. exercise) or assessed combination therapies (drugs plus exercise). One strategy future trials should consider is combining effective treatments from different categories of intervention. We note that PCORI has funded a trial comparing CBT, modafinil, and CBT with modafinil. However, given the relative strength of exercise interventions, future trials should include combination therapies involving exercise as well. We had hoped to explore the impact of cotreatments for MS on fatigue and quality of life. Unfortunately, only a single RCT examined cotreatments as a potential modifier of the primary intervention’s effect. Many exercise, educational and behavioral interventions can be provided in multiple delivery modes. For instance, CBT and exercise may be delivered in group or individual settings, in clinics or at home. Delivering educational interventions such as a fatigue management program online or through phone calls may offer significant benefits to patients (particularly those with mobility problems), may allow wider dissemination, and may require fewer resources. While we identified some literature comparing different modes of delivery, more high quality trials are needed. Finally, traditionally, evidence‐based medicine has not prioritized translating information into interactive tools to promote informed, shared decision‐making for policymakers, clinicians and patients.

The use of evidence maps to distill the results of a comprehensive literature search and data synthesis into an interactive Web‐based format may be a significant step forward. Important next steps should include pilot testing with qualitative feedback to identify potential improvements for usability and prioritizing content.

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46 Appendices Appendix A. Literature Search Methods

Literature Search: In November 2017, we conducted a literature review to identify research focused on treating fatigue in persons with multiple sclerosis. Our search protocol included PubMed, EMBASE/Medline, and PsycINFO. We also searched the National Guideline Clearinghouse to identify clinical practice guidelines that addressed this topic. We present the strategies in Embase.com syntax (using EMTREE) in the tables below. We translated the controlled vocabulary terms and syntax for the PubMed and PsycINFO searches.

Clinical Trials and NIH Funding Announcements: To identify additional trials in this topic area, we searched ClinicalTrials.gov and the PCORI website through August 21, 2018. Search terms used for ClinicalTrials.gov include: (“multiple sclerosis” OR MS OR RRMS OR PPMS OR SPMS) AND patient‐centered outcomes [Sponsor] Multiple sclerosis AND fatigue

Bibliographic search strategies: Embase.com [1987 ‐ 2017] – Drug therapy

Set Concept Search Statement # Identified Number 1 MS 'multiple sclerosis'/de OR 'multiple sclerosis':ti OR 'ms':ti OR 140161 'ppms':ti OR 'rrms':ti OR 'spms':ti 2 Fatigue 'fatigue'/de OR 'asthenia'/de OR 'exhaustion'/de OR 'muscle 193902 fatigue'/de OR 'lassitude'/de 3 asthenia:ti,ab OR exhaust*:ti,ab OR fatigue*:ti,ab OR 187421 lassitude:ti,ab OR legasthenia:ti,ab OR fatigability:ti,ab OR tired*:ti,ab 4 Combine sets – #2 OR #3 286132 fatigue 5 Combine sets – #1 AND #4 6340 MS fatigue 6 Limit by date, 5517 English language, human population 7 Drug - ‘amantadine’/de OR ‘memantine’/de OR (amantadin* OR adekin 25453 Amantadine OR amanta* OR amixx OR cerebramed OR endantadine OR infex OR mantadix OR midantan OR symadine OR symmetrel OR viregyt OR wiregyt OR tregor OR adamantan* OR amandin* OR boidan OR contenton OR enzil OR mandatan OR mantadix OR mantidan OR midantane OR protexin OR virofral OR virosol OR virucid):ti,ab

Set Concept Search Statement # Identified Number 8 Drug - ‘aminopyridine derivative’/de OR (aminopyridines OR ‘4- 8301 Aminopyridines aminopyridine’ OR fampridine* OR pymadine* OR ‘VMI-103’ OR amrinone OR Amrinon OR cordemcura OR inocor OR wincoram):ti,ab 9 Drug – aspirin ‘acetylsalicylcic acid’/de OR (aspirin OR acetylsalicylic acid OR 192796 acetysal OR acylpyrin OR aloxiprimum OR colfarit OR dispril OR easprin OR endosprin OR magnecyl OR micristin OR polopirin OR polopiryna OR solprin OR solupsan OR zorprin OR acenterine OR acesal OR acetan OR aceticil OR aceticyl OR acetilum OR acetony OR acetylin OR acetylo OR acetylon OR acetylosalicylicum OR actorin OR acytosal OR actorin OR adiro OR alabukun OR alasil OR albyl OR anthrom OR aptor OR arthralgyl OR astrix OR bamyl OR bayasprinia OR bayer OR bebesan OR biprin OR bokey OR boxazin OR bufferin OR cafenol OR caprin OR cardiosa OR cardioaspirina OR cardioflow OR cartia OR caspirin OR catalgine OR catalgix OR cemerit OR claradin OR claragine OR colfarit OR comoprin OR contrheuma OR darosal OR dispirin OR dolean OR durlaza OR dusil OR ecasil OR ecosprin OR ecotrin OR egalgic OR emocin OR empirin OR encaprin OR encine OR enodprin OR entaprin OR entericin OR enteroprin OR enterosarine OR enterospirine OR entrophen OR eskotrin OR euthermine OR extern OR flamascard OR genasprin OR globentyl OR godamed OR gotosan OR helicon OR hjertemagnyl OR idotyl OF infatabs OR istoprin OR istopyrine OR ivepirine OR juvepirine OR keypo OR kilios OR kinderaspirin OR measurin OR mejoral OR melabon OR micropyrin OR migrasaa OR mikristin OR miniasal OR mycristin OR naspro OR novasen OR ostoprin OR pancemol OR paracin OR paynocil OR pengo OR plewin OR polopiryna OR premaspin OR primaspan OR proprin OR pyronoval OR reumyl OR rhodine OR rhonal OR salacetin OR salacetogen OR saletin OR salisalido OR salospir OR sargepirine OR sedergine OR soldral OR solpyron OR solucetyl OR solupsa OR spren OR tapal OR tevapirin OR toldex OR treupahlin OR treuphalin OR tromalyt OR tromcor OR turivital OR vitalink OR xaxa):ti,ab 10 Drug – bupropion ‘amfebutamone’/de OR (bupropion OR amfebutamone OR 16880 quomen OR Wellbutrin OR zyban OR zyntabac OR aplenzin OR budeprion OR buprion OR bupropin OR buxom OR forfivo OR odranal OR wellbatrin):ti,ab

Set Concept Search Statement # Identified Number 11 Drug – hypnotics 'hypnotic sedative agent’/exp or barbituates/exp OR (alprazolam 420340 and sedatives OR alprazolam OR alprox OR cassadan OR asparon OR kalma OR ralozam OR tafil OR Xanax OR chlordiazepoxide OR chlozepid OR elenium OR Librium OR methaminodiazepoxide OR clorazepate OR tranxene OR tranxilium OR estazolam OR nuctalon OR ProSom OR tasedan OR medazepam OR nobrium OR rudotel OR rusedal OR midazolam OR dormicum OR versed OR triazolam OR halcion OR trilam OR acecarbromal OR abasin OR adityl OR paxarel OR sedamyl OR sedmynol OR acetophenone OR hypnone OR allobarbital OR allobarbitone OR alnox OR barballyl OR barbidal OR curral OR diadol OR dial OR diallymal OR dialume OR malilum OR amobarbital OR amsal OR amytal OR barbamyl OR eunoctal OR isonal OR pentymal OR placidel OR transital OR barbital OR barbitone OR diemal OR dormileno OR ethylbarbital OR medinal OR veronal OR hexobarbital OR evipan OR hexenal OR hexobarbitone OR mephobarbital OR mebaral OR prominal OR methohexital OR brevimytal OR brevital OR brietal OR methohexital OR methohexitone OR pentobarbital OR diabutal OR etaminal OR ethaminal OR mebubarbital OR mebumal OR nembutal OR pentobarbitone OR sagatal OR phenobarbital OR gardenal OR hysteps OR luminal OR phenemal OR phenobarbitone OR primidone OR liskantin OR misodine OR mizodin OR mysoline OR primaclone OR resimatil OR sertan OR secobarbital OR meballymal OR quinalbarbitone OR sebar OR seconal):ti,ab 12 Drug – interferon ‘beta interferon’/de OR (interferon NEAR/2 beta) 28883 beta 13 Drug - modafinil ‘modafinil’/de OR (Modafinil OR alertec OR modiodal OR 5429 Provigil OR sparlon OR vigil OR armodafinil OR attenace OR modasomil OR modavigil OR vigicer):ti,ab 14 Drug – Natalizumab/de OR (natalizumab OR antegren OR tysabri):ti,ab 8225 natalizumab 15 Drug – pemoline Pemoline/de OR (azoxodone OR betanamin OR ceractiv OR 1853 cyclert OR deltamine OR dynalert OR fenoxazal OR hyperilex OR hyton OR kethamed OR pemolert OR pemoline OR phenoxazole OR pioxol OR ronyl OR tradon OR volital):ti,ab 16 Drug – prokarin ‘Prokarin’ 9 17 Drug ‘Teriflunomide’ 1854 teriflunomide 18 Combine sets – #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR 681612 drugs #15 OR #16 OR #17 19 Combine sets - #6 AND #18 1516 20 Therapy ‘therapy’/exp 7376563 21 Combine sets #6 and #20 2975 22 #20 NOT #22 410 23 - 25 #22 AND [medline]/lim - 264 146 #22 AND [Embase]/lim - #24 NOT #23 26 Reviews #25 and (review/de OR ((systematic NEAR/2 review*) 40 or (meta NEAR/2 analy*)))

Set Concept Search Statement # Identified Number 27 #25 NOT (abstract:nc OR annual:nc OR 'book'/exp OR 76 conference:nc OR 'conference abstract':it OR 'conference paper'/exp OR 'conference paper':it OR 'conference proceeding':pt OR 'conference review':it OR congress:nc OR 'editorial'/exp OR editorial:it OR 'erratum'/exp OR letter:it OR 'note'/exp OR note:it OR meeting:nc OR sessions:nc OR 'short survey'/exp OR symposium:nc) 28 #27 NOT #26 37 29 #28 NOT ‘case report’/de 35

Set Concept Search Statement # Identified Number 1 MS 'multiple sclerosis'/de OR 'multiple sclerosis':ti OR 'ms':ti OR 140649 'ppms':ti OR 'rrms':ti OR 'spms':ti 2 Fatigue 'fatigue'/de OR 'asthenia'/de OR 'exhaustion'/de OR 'muscle 194026 fatigue'/de OR 'lassitude'/de 3 asthenia:ti,ab OR exhaust*:ti,ab OR fatigue*:ti,ab OR 190256 lassitude:ti,ab OR legasthenia:ti,ab OR fatigability:ti,ab OR tired*:ti,ab 4 Combine sets – #2 OR #3 287716 fatigue 5 Combine sets – #1 AND #4 6348 MS fatigue 6 Limit by date, 5518 English language, human population 7 CAM – general ‘Dietary supplement’/de OR ‘plant medicinal product’/exp OR 1371008 ‘medicinal plant’/exp 8 CAM – carnitine Carnitine/de OR carnitine OR levocarnitine OR (levo NEAR/1 23049 carnitine) 9 CAM – coenzyme ((coenzyme OR ‘co-enzyme’) NEAR/1 Q10) OR ubiquinone OR 21678 Q10 ubisemiquinone OR ubiten 10 CAM – vitamin A ‘vitamin A’ OR tretinoin OR aquasol OR retinol 60136 11 CAM - (andrographis NEAR/2 paniculata) OR andrographis/de 1683 Andrographis paniculata 12 CAM – Thiamine/de OR (sulbutiamine OR viaverm) 19607 sulbutiamine 13 CAM - ginseng Ginseng/de OR (ginseng OR ‘jen shen’ OR ninjin OR renshen 9978 OR schinseng OR shinseng):ti,ab 14 CAM – Acupuncture/exp OR (acupuncture OR pharmacopuncture OR 45450 Acupressure shiatsu OR ‘tui-na’) Acupuncture 15 CAM – cryotherapy/de OR (cryotherap* OR cryotreatment OR cryogenic 23099 cryotherapy OR “cold therapy” OR cryotherm*):ti,ab 16 CAM – mind/body Meditation/de OR ‘relaxation training’/de OR Meditat*:ti,ab OR 25671 techniques (relax* NEAR/2 (therap* OR method* OR technique* OR training))

Set Concept Search Statement # Identified Number 17 Devices transcranial magnetic stimulation/exp OR (repetitive NEAR/2 26851 magnetic) OR rTMS OR (transcranial NEAR/2 (direct OR magnetic)) or tDCS or (electrotherapy/de AND (transcranial OR repetitive):ti) 18 Neurofeedback/de OR Neurofeedback:ti,ab OR ((alpha OR 4474 brainwave OR EEG OR electroencephalograph* OR electromyograph*) NEAR/2 (feedback OR biofeedback)) 19 Self-management self care/exp OR (self NEAR/4 (care OR efficac* OR manag* OR 19970 monitor*)):ti 20 Patient education ‘patient education’/de OR (patient adj2 educat*) 100687 21 Combine sets #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR 1708252 #15 OR 20 22 Combine sets 7 AND 22 566 23 Therapy ‘therapy’/exp 7382172 24 Combine sets 7 and 23 2977 25 Eliminate overlap 23 not 24 144 26 Limits #25 NOT (abstract:nc OR annual:nc OR 'book'/exp OR 102 conference:nc OR 'conference abstract':it OR 'conference paper'/exp OR 'conference paper':it OR 'conference proceeding':pt OR 'conference review':it OR congress:nc OR 'editorial'/exp OR editorial:it OR 'erratum'/exp OR letter:it OR 'note'/exp OR note:it OR meeting:nc OR sessions:nc OR 'short survey'/exp OR symposium:nc) 27 #26 and (review/de OR ((systematic NEAR/2 review*) or (meta 38 NEAR/2 analy*))) 28 #26 NOT #27 64 29 #28 AND ‘case report’/de - 3 61 #29 AND (case NEAR/2 series) – 0 #28 NOT #29 30 #29 AND [medline]/lim 47 31 #31 NOT #32 14 32 Exclude overlap 11 with PCOR5 drug search strategy

National Guideline Clearinghouse

MeSH browse – multiple sclerosis

Search: S1: “multiple sclerosis”

51 Appendix B. Included and Excluded Interventions Included Interventions Pharmacologic Exercise Behavioral/Education CAM Combination Other  Amantidine  Aerobic, balance and  Mindfulness-based  Electromagnetic field  Aerobic, moderate  Non-invasive brain  Modafinil stretching exercises training (e.g., meditation) therapy progressive stimulation (i.e.,  Armodafinil (including yoga)  Cognitive behavioral  Cooling therapy resistance activity transcranial combined with CBT magnetic stimulation,  Detroamphetamine +  Supervised exercise therapy (CBT)  Cannabinoids (e.g., transcranial direct Amphetamine programmes involving  Group psychotherapy THC:CBD oromucosal current stimulation) (Adderall) moderate progressive  Relaxation therapy spray) resistance training  Continuous positive  Dextroamphetamine (including progressive  cannabis airway pressure (dexedrine)  Aquatic exercise muscle relaxation)  lofepramine plus (CPAP)  L-dexamfetamine  Vestibular  Cognitive rehabilitation phenylalanine with rehabilitation  Methylphenidate  Neuropsychological B12  Climbing exercise  4-aminopyridine training program  magnetic therapy (dalfampridine,  Treadmill exercise Education  low fat diet with fampridine)  Inspiratory exercise  Energy conservation omega-3  L-carnitine  Balance training programs supplementation (or omega-3  Aspirin (including Falls  Fatigue management Prevention Program) supplementation)  3, 4 diaminopyridine programs (self-  Acupuncture (DAP)  Gait training (including management, self-care) robotic assisted)  Histamine  Exercise counseling  Rehabilitation programs (e.g., education  Histamine + Caffeine programs (except for or motivational or online)  Paroxetine cognitive rehab)  Online interactive  Buproprion  Physical Therapy exercise motivational  Fluoxetine (including use of program + Pedometer  Sertraline motor imagery and  Occupational therapy  Duloxetine rhythmic auditory  FACETS (Fatigue: stimulation) Applying Cognitive Behavioral and Energy Self effectiveness Techniques to lifeStyle)

Excluded Interventions

Acupressure Hypnotherapy Alemtuzumab Lipoic acid Andrographis paniculata Lisdexamfetamine dimesylate Angioplasty/venoplasty for central chronic venous Lithium insufficiency Low fat plant based diet, low fat diet Art therapy Low level laser therapy B-alanine Massage therapy Bee venom MD 1003 Biofeedback stress management Mechanical focal vibration Biofeedback/Neurofeedback Melatonin Coenzyme Q/MitoQ Methylprednisone Constraint induced movement therapy Modified Paleo diet Cryostimulation Motivational interviewing D-aspartate N-acetyl cysteine Dietary counseling Naturopathy medicine Diet high in omega 3 fatty acids, polyphenols, Neuromuscular taping antioxidants, without refined sugars Peginterferon Beta 1a Dimethyl fumarate Pemoline Dorsiflexion assisted orthosis Ponesimide Duloxetine Reflexology Emotion focused therapy Riluzole Fingolimod Rivastigmine Gingko biloba Social cognitive treatment Functional electrical stimulation Stem cell transplant Ginseng Sulbutiamine Green tea catechins Support groups (web based or face to face) High flavonoid cocoa Thinking prompts added to gait training High voltage pulsed galvanic stimulation Teriflunomide Hippotherapy Tizanidine Hydrotherapy Transcranial random noise stimulation Hyperbaric oxygen Vitamin A Vitamin D Week-long educational by physicians

Appendix C. Related PCORI‐funded Projects and clinicaltrials.gov records Table 3. Related PCORI-funded Projects Author Title Start Date NCT Number Study Number Category of Specific Outcomes and Design of Intervention Intervention Projected Patients End Date Backus, D Comparative Effectiveness Study July 2018 NCT03468868 RCT 500 Exercise Resistance and Timed 25 foot walk, Telerehab Versus Conventional to Jan cardio exercise, Neuro QOL, Modified 2022 supervised vs. Fatigue Impact Scale home Plow MA Comparing the Effectiveness of Sep 2017 NA RCT 610 Behavioral/Educ Managing fatigue Fatigue; QOL Fatigue Management Programs to Sep ation course: face-to- for People with MS 2021 face vs. teleconference vs. internet Nourbakhsh B, Comparing Three Medicines to July 2016 NCT03185065 RCT 136 Pharmacologic Amantadine; Fatigue; QOL; Raj Revirajan N Treat Fatigue in Patients with to Sep Modafinil; Sleepiness Multiple Sclerosis (MS) 2020 Methylphenidate; Placebo Braley T, A Randomized Controlled Trial of Sep 2017 NA NR NR Behavioral/Educ Cognitive Fatigue; depression; Kratz A Telephone-Delivered Cognitive to June ation; behavioral disability; sleep Behavioral Therapy, Modafinil, 2021 Pharmacologic; therapy; disturbance and Combination Therapy of Both Combination modafinil Interventions for Fatigue in Multiple Sclerosis Rimmer J Comparing Clinic- and Home- July 2016 NCT03117881 RCT 820 Exercise In-person QOL; physical activity; Based Exercise Programs to to Nov supervised pain; fatigue; balance; Help Adults with Multiple 2021 exercise; online endurance; gait; Sclerosis exercise support strength Ehde DM Improving the Quality of Care for May 2014 NCT02137044 RCT 200 Behavior/Educat Care Pain; depression; Pain and Depression in Persons to Mar ion coordination fatigue; hrQOL; delta With Multiple Sclerosis 2017 depression care; delta depression severity; delta pain severity; delta disability; delta satisfaction with care NA – Not available NR – Not reported

Table 4. Related Records in clinicaltrials.gov NCT Number Title Start Date Study Number Intervention(s) Outcomes and Design of Projected Patients End Date NCT01611987 The Role of Exercise in Modifying Sep 2012 to RCT 240 Supervised Oxygen consumption; muscle strength measured Outcomes for People With Multiple Dec 2018 aerobic exercise with Biodex; 6 Minute Walk test (6MWT); Anaerobic Sclerosis leg power; Patient Determined Disease Steps (PDDS); Change in fatigue levels; Rand 36; EQ-5D; Patient generated Index; Exercise Self-Efficacy Scale; Change in perception about exercise benefits and exercise barrier; Modified Canadian Aerobic Fitness test NCT01698086 Vestibular Rehabilitation for Persons Oct 2012 to RCT 88 Multidisciplinary Balance (Dynamic Posturography/Computerized With Multiple Sclerosis: Who Benefits Nov 2018 rehabilitation Sensory Organization Test); Visual Stability the Most? (MSVR3trial) (Dynamic Visual Acuity and Gaze Stabilization Test); Perceived fatigue (Modified fatigue Impact Scale) NCT01746342 Sleep Apnea in Multiple Sclerosis Feb 2013 to RCT 65 CPAP Fatigue Severity Scale; Fatigue Scale for Motor and Positive Airway Pressure Trial Mar 2019 Cognitive Functions; Epworth Sleepiness Scale; Pittsburgh Sleep Quality Index; Pain visual analog scale; Multiple Sclerosis-specific quality of life measure-54 (MSQOL-54); Expanded Disability Status Scale; Center for Epidemiological Studies- Depression Scale; Cognitive evaluation; Polysomnographic variables; Objective CPAP compliance NCT02391961 Study and Treatment of Visual Apr 2015 to RCT 30 4-aminopyridine Eye movement assessment; Visual function Dysfunction and Motor fatigue in Mar 2019 assessment; Gait assessment; Visual disability Multiple Sclerosis assessment; Quality of life assessment NCT02421731 Robot-assisted Gait Training on Feb 2014 to RCT 98 Robot-assisted Six-Minute Walking Test ; Berg Balance Scale ; Up Mobility in Severely Disabled Multiple Feb 2018 gait training and Go Test ; Fatigue Severity Scale ; Modified Sclerosis Patients Ashworth Scale ; Short-Form 36 ; Haemodynamic measurements ; Metabolic measurements by Near infrared spectroscopy ; Circulating biomarkers NCT02425644 Oral Ponesimod Versus Teriflunomide Jun 2015 to RCT 1100 Ponesimod vs. Annualized relapse rate (ARR); Time to 12-week In Relapsing Multiple Sclerosis May 2019 terifunomide confirmed disability accumulation (CDA); Percent change in brain volume (PCBV); Time to first confirmed relapse; Cumulative number of combined unique active lesions; Change from baseline to Week 108 in fatigue-related symptoms

Table 4. Related Records in clinicaltrials.gov, continued

NCT Number Title Start Date Study Number Intervention(s) Outcomes and Design of Projected Patients End Date NCT02440516 Standardized Ambulatory Feb 2016 to RCT 62 Fatigue Change from baseline in Multiple Sclerosis Impact Neurorehabilitation Program for Jul 2018 management Scale 29 (MSIS-29); Change from baseline in Coin Patients With Multiple Sclerosis program Rotation Task (Heldner et al. 2014); Change from baseline in Timed Up and Go (TUG) (Nilsagard et al. 2007); Change from baseline in Nine-hole-Peg Test (NHPT) (Gookin et al. 1988); Change from baseline in 25-Foot Walk Test (25-FWT) (Cohen et al. 2014); Change from baseline in EDSS; Change from baseline in Rand 36; Change from baseline in fatigue Severity Scale NCT02496416 Aquatic Exercise Intervention in Aug 2016 to RCT 15 Aquatic exercise Cognition measured by results of standardized Multiple Sclerosis Dec 2018 neuropsychological tests; fatigue measured by self- report questionnaires; Quality of Life measured by self-report questionnaires NCT02538094 tDCS and Cognition in Adults With Sep 2014 to RCT 50 Transcranial Cognition; fatigue Multiple Sclerosis or Encephalitis Sep 2018 direct current stimulation

56 Table 4. Related Records in clinicaltrials.gov, continued

NCT Number Title Start Date Study Number Intervention(s) Outcomes and Design of Projected Patients End Date NCT02583386 Comprehensive Fall Prevention and Apr 2016 to RCT 94 Exercise and Change from Baseline in Self-Reported Falls and Detection in Multiple Sclerosis May 2019 educational Fall-Related Injuries at Completion of Program and program the Following Six Months; Change from Baseline in Balance Confidence; Change from Baseline in Satisfaction with Participation in Social Roles; Change from Baseline in Ability to Participate in Social Roles and Activities; Change from Baseline in Quality of Life; Accuracy and Impact of Fall Detection and Localization by the MobileRF Fall Detection System, Compared to Paper Fall Calendars; Change from Baseline in Mobility and Balance (TUG score) at Completion of Program and the Following Six Months; Change from Baseline in Mobility and Balance (FSST score) at Completion of Program and the Following Six Months; Change from Baseline in Level of Physical Activity at Completion of Program and the Following Six Months; Change from Baseline in Fall Prevention Strategy at Completion of Program and the Following Six Months; Change from Baseline in fatigue at Completion of Program and the Following Six Months; Change from Baseline in Mobility at Completion of Program and the Following Six Months; Change from Baseline in Psychosocial Function at Completion of Program and the Following Six Months; Change from Baseline in Knowledge and Confidence Regarding Fall Prevention at Completion of Program and the Following Six Months NCT02607020 Self-Management Program Based on Dec 2015 to RCT 100 Unsupervised Fatigue; Change in fatigue; Safety (Number of Physical Exercises in People With Jan 2020 aerobic exercise patients with adverse events related to treatment); Multiple Sclerosis vs. relaxation Change in MS-specific health related quality of life; training Change in walking capacity; Change in plasmatic cytokines: IFNg; Change in plasmatic cytokines: TNFa; Adherence; Amount of physical activity performed; Change in Cardiorespiratory fitness; Change in Lower limbs spasticity; Change in objective walking endurance; Change in static and dynamic balance; Change in Neurological Disability

57 Table 4. Related Records in clinicaltrials.gov, continued

NCT Number Title Start Date Study Number Intervention(s) Outcomes and Design of Projected Patients End Date NCT02634567 Attention/Working Memory Apr 2016 to RCT 30 Unsupervised Paced Auditory Serial Addition Test; Symbol Digit Rehabilitation in Multiple Sclerosis: A Dec 2018 aerobic exercise Modalities Test; Stroop colour word test; Judgement Pilot Project Using Cogmed Working of Line Orientation; Controlled Oral Word Association Memory Training Test; California Verbal Learning Test; Brief Visual Memory Test; Delis-Kaplan Executive Function System Sorting Test; Beck Depression Inventory - Fast Screen; Hospital Anxiety and Depression Scale; fatigue Severity Scale; Short Form Health Survey; Dysexecutive Questionnaire; Cognitive Failures Questionnaire; BRIEF Cope; Social Stress and Support Interview; Multiple Sclerosis Neuropsychological Screening Questionnaire; Perceived Deficits Questionnaire; Visual Spatial Span Board Assessment; Digit Span; Arithmetic; 19.Letter-Number Sequencing NCT02726672 fatigue and Inspiratory Muscles Feb 2016 to RCT 60 Respiratory Fatigue graded according to EMIF-SEP Training in Patients With Multiple May 2019 rehabilitation questionnaire; Sleep disorders graded according to Sclerosis the Epworth Sleepiness Scale; Quality of life graded according to the SEP-59 questionnaire; Maximal inspiratory pressure graded according to the Black and Hyatt method; Maximal expiratory pressure graded according to Black and Hyatt method; Forced vital capacity (FVC) graded with a portable spirometer; Tidal volume graded with a portable spirometer; Forced expiratory volume in one second (FEV1) graded with a portable spirometer; FEV1/FVC ratio graded with a portable spirometer; Energy consumption during repeated effort; Depression graded according to the French version of the Beck Depression Inventory Fast-Screen; Swallowing problems graded according to the DYMUS score; Level of disability graded by the EDSS (Expanded Disability Status Scale); Collection of the drug treatments received evaluated by a questionnaire NCT02740361 Online Program to Reduce Feb 2017 to RCT 400 CBT alone vs. Beck Depression Inventory-II; WHO Quality of Life Depression in MS Apr 2019 CBT + weekly scale (WHO-QOL BREF); Multiple Sclerosis Impact emails vs. Scale (MSIS); fatigue Scale for Motor and Cognitive waitlist Functions (FSMC); Chalder fatigue Scale

58 Table 4. Related Records in clinicaltrials.gov, continued

NCT Number Title Start Date Study Number Intervention(s) Outcomes and Design of Projected Patients End Date NCT02870023 How Does Strength Training and Jun 2016 to RCT 90 Resistance Change in gait speed measured by "Six Spot Step Balance Training Affect Gait Function Dec 2018 training vs. Test"; Change in gait speed measured by "Timed 25 and fatigue in Patients With Multiple balance training Foot Walk"; fatigue; Endurance; Self-evaluated gait Sclerosis? vs. no treatment function; Temporospatial measures; Balance - static; Balance - functional; Balance - confidence; Strength NCT02874677 A Reeducation Program to Effort to Oct 2017 to RCT 88 Supervised Distance estimated by the 6 minute Walk Test; Improve the Walking of Multiple May 2020 aerobic exercise Walking speed measured by the timed 25-ft walk test Sclerosis Patients (T25FWT); Heart rate estimation at the end of the 6 minute walk test; Walking perception measured by the Twelve Item MS Walking Scale (MSWS-12) scale; Effort test for the estimation of the maximal consumption of oxygen (O2max); Multiple sclerosis- 59 French scale for the estimation of the quality of life; fatigue Impact Scale (EMIF-SEP); Effort test for the estimation of the ventilatory threshold (VT1) NCT03174379 A Study to Analyze the Effect of Jun 2017 to RCT 30 Acupuncture Fatigue severity scale; Medical Outcomes Study Pain Acupuncture on Mobility And Quality Jul 2019 Effects Scale; Gait measured by 6-minute walk test; of Life in Multiple Sclerosis Balance measured by 25-foot walk test NCT03244696 Behavior and Activity Monitoring in Nov 2017 to RCT 200 Step count Change in Cognitive Performance on Minimal MS Jan 2020 monitoring vs. Assessment of Cognitive Function in Multiple water tracking Sclerosis (MACFIMS); Changes in the Functional Architecture of the MS Brain; Change in Cognitive Performance on the NIH Cognitive Toolbox Battery; Change in Cognitive Performance on Subtests of the Wechsler Adult Intelligence Scale-IV; Change in inflammatory biomarkers; Improvements on a Self- Report Measure of Depression; Improvements on a Self-Report Measure of Anxiety; Improvements on a Self-Report Measure of Perceived Stress; Improvements on a Self-Report Measure of Quality of Life; Improvements on a Self-Report Measure of Sleep Quality; Improvements on a Self-Report Measure of fatigue NCT03322761 Early Exercise Efforts in Multiple Apr 2018 to RCT 166 Education on Change in Annual Relapse Rate (ARR); Percentage Sclerosis Sep 2020 physical activity brain volume change; Multiple Sclerosis Functional vs. supervised Composite (MSFC); Expanded Disability Status aerobic exercise Scale (EDSS) score

59 Table 4. Related Records in clinicaltrials.gov, continued

NCT Number Title Start Date Study Number Intervention(s) Outcomes and Design of Projected Patients End Date NCT03353974 Video Games Therapy on Balance Dec 2017 to RCT 40 Video game Timed Up and Go (TUG) test; Four Square Step Test and Cognitive Functions in Mild to Dec 2018 therapy vs. (FSST); Functional Reach Test (FRT); Berg Balance Moderate Impaired Multiple Sclerosis balance platform Scale (BBS); Dynamic Gait Index (DGI); Modified Patients. therapy fatigue Impact Scale (MFIS); Multiple Sclerosis Walking Scale-12 (MSWS-12); Multiple Sclerosis Impact Scale-29 (MSIS-29); Functional Assessment of Multiple Sclerosis (FAMS); Beck Depression Inventory-Second Edition (BDI-II); State Trait Anxiety Inventory (STAI-Y); Intrinsic Motivation Inventory (IMI); Go-No Go - Test of Attentional Performance T.A.P; Test of Attentional Performance T.A.P; Paced Auditory Serial Addition Test (PASAT); Stroop Color- Word Test (SCWT); Symbol Digit Modalities Test (SDMT); Instrumented Basic Balance Evaluation (IBBE); Instrumented Dual Task (IDT); Muscle Synergies Analysis; Functional Near Infrared Spectroscopy (fNIR NCT03389217 Efficacy of tDCS on Pain in Multiple Dec 2017 to RCT 30 Transcranial Numeric Rating Scale (NRS); Short Form McGill Pain Sclerosis Dec 2018 direct current Questionnaire (SF-MPQ); Brief Pain Inventory (BPI); stimulation + Pain Catastrophizing Scale (PCS); Coping Strategies rehabilitation vs. Questionnaire (CSQ); Beck Depression Inventory II sham + (BDI-II); MS Quality of Life - 54 (MSQOL-54); fatigue rehabilitation Severity Scale (FSS); Go/No-go Task; Patient Global Impression of Change (PGIC); Pressure Pain Threshold (PPT); Electroencephalography (EEG) recordings NCT03444454 Telerehabilitation in Multiple Sclerosis Feb 2018 to RCT 96 Supervised Change in measure of quality of life; Change in Jan 2019 aerobic exercise balance; Change in gait; Change gross manual dexterity; Change in global cognitive status; Change cognitive status; Change in fatigue; Change in Emotional Traits; Change in Behavioral (depression); Change in Behavioral (anxiety)

60 Table 4. Related Records in clinicaltrials.gov, continued

NCT Number Title Start Date Study Number Intervention(s) Outcomes and Design of Projected Patients End Date NCT03471338 Neuropsychological Management of Oct 2017 to RCT 40 Cognitive Efficacy of cognitive rehabilitation on quality of life at Multiple Sclerosis: Benefits of a Dec 2019 training short term; Efficacy of cognitive rehabilitation on Computerised Semi-autonomous At- quality of life at long term; Efficacy of cognitive home Cognitive Rehabilitation rehabilitation on self-esteem at short term; Efficacy of Programme cognitive rehabilitation on self-esteem long term; Efficacy of cognitive rehabilitation on depression at short term; Efficacy of cognitive rehabilitation on depression at long term; Efficacy of cognitive rehabilitation on cognition at short term; Efficacy of cognitive rehabilitation on cognition at long term; Efficacy of cognitive rehabilitation on metacognition at short term; Efficacy of cognitive rehabilitation on metacognition at long term; Efficacy of cognitive rehabilitation on fatigue at short term; Efficacy of cognitive rehabilitation on fatigue at long term; Efficacy of cognitive rehabilitation on sleep at short term; Efficacy of cognitive rehabilitation on sleep at long term; Efficacy of cognitive rehabilitation on anxiety at short term; Efficacy of cognitive rehabilitation on anxiety at long term.

61 Table 4. Related Records in clinicaltrials.gov, continued

NCT Number Title Start Date Study Number Intervention(s) Outcomes and Design of Projected Patients End Date NCT03490240 Project BIPAMS: Behavioral Mar 2018 to RCT 280 General Change of Physical Activity levels through Intervention for Physical Activity in Mar 2021 education vs. Accelerometery from baseline at 6 and 12 months; Multiple Sclerosis education on Change of Physical Activity levels through the Godin physical activity Leisure-Time Exercise Questionnaire from baseline at 6 and 12 months; Change of Physical Activity levels through the Abbreviated International Physical Activity Questionnaire from baseline at 6 and 12 months; Change of self-report measures of walking through the Multiple Sclerosis Walking Scale - 12 from baseline at 6 and 12 months; Change of self- report measures of Walking through the Patient Determined Disease Steps Scale from baseline at 6 and 12 months; Change of self-report measures of Cognition through the Perceived Deficits Questionnaire from baseline at 6 and 12 months; Change of self-report measures of Cognition through the Multiple Sclerosis Neuropsychological Questionnaire from baseline at 6 and 12 months; Change of self-report measures of fatigue through the fatigue Severity Scale from baseline at 6 and 12 months; Change of self-report measures of fatigue through the Modified fatigue Impact Scale at 6 and 12 months from baseline; Change of self-report measures of Anxiety and Depression through the Hospital Anxiety and Depression Scale at 6 months and 12 months from baseline; Change of self-report measures of Pain through the Short-form of McGill Pain Questionnaire at 6 and 12 months from baseline; Changes of self-report measures of sleep through the Pittsburgh Sleep Quality Index at 6 and 12 months from baseline; Changes of self-report measures of quality of life through the Medical Outcomes Study Short Form-36 at 6 and 12 months from baseline; Changes of self-report measures of quality of life through the Multiple Sclerosis Impact Scale-29 at 6 and 12 months from baseline. NCT03492450 Unraveling Early Walking Dysfunction Apr 2018 to RCT 40 Supervised Change in Six Minutes Walking Test; Change in in Non-disabled MS People: Jun 2020 aerobic exercise Instrumented variables; the Twelve-Item Walking Assessment and Potential Scale; the Twenty-five-foot walking test; The fatigue Therapeutic Interventions Severity Scale; the Nine hole peg test

62 Table 4. Related Records in clinicaltrials.gov, continued

NCT Number Title Start Date Study Number Intervention(s) Outcomes and Design of Projected Patients End Date NCT03501342 Effects of Immersive Virtual Reality on Apr 2018 to RCT 30 Virtual reality vs. Berg Balance Scale; Timed Up and Go Test; Balance, Mobility, and fatigue in Jun 2020 dynamic Modified Sensory Organization Test; One-leg Patients With Multiple Sclerosis balance training standing duration; Activities-specific Balance vs. no treatment Confidence; fatigue Severity Scale; fatigue Impact Scale NCT03521557 Gaze and Postural Stability in Multiple May 2018 to RCT 50 Gaze and Dizziness Handicap Inventory; Dizziness Handicap Sclerosis Sep 2020 postural stability Inventory Follow-up; Activity Specific Balance exercises Confidence Scale; Functional Gait Assessment; Mini- BEST test; Dynamic Visual Acuity; Passive Angular Vestibulo-ocular Reflex Gain; Compensatory Saccade Frequency; Compensatory Saccade Latency; Gaze Position Error; Margin of stability; Step Latency; Postural Sway NCT03544177 Effects of Low-intensity Interval May 2018 to RCT 40 Supervised Timed 25-foot Walk test; 6-Minute Walking Test; Walking With Blood Flow Restriction Jul 2021 aerobic exercise Berg Balance Scale; 5-time Sit-to-Stand test; Multiple on Functional Capacity in Multiple interval walking Sclerosis Impact Scale; fatigue Severity Scale; Short Sclerosis vs. Supervised Form Health Survey 36 aerobic exercise conventional NCT03638739 Exercise and Brain Health in MS Aug 2018 to RCT 10 Supervised Change in Perceived fatigue; Change in Jun 2019 aerobic exercise Inflammatory Markers; Change in Depression; Change in Cognition; Change in Aerobic Capacity; Change in Muscle Strength; Change in Perceived Quality of Life (QOL) MS – Multiple Sclerosis RCT‐ Randomized controlled trial tDCS transcranial direct current stimulation

Appendix D. Evidence Tables Table 5. Data for Evidence Map 1 (Abstracts on Interventions for Fatigue in MS) Reference Intervention Type of Intervention Specific Intervention Total Number US or Category Patien Assigned Non-US ts in to This Study Study Treatment Group van den Akker et al. Behavioral/Education Cognitive behavioral CBT 91 44 Non-US (2017)38 therapy (CBT) Kiropoulos et al. (2016)46 Behavioral/Education Cognitive behavioral CBT 30 15 Non-US therapy van Kessel et al. (2008)64 Behavioral/Education Cognitive behavioral CBT 72 35 Non-US therapy Mohr et al. (2003)65 Behavioral/Education Cognitive behavioral CBT 71 23 US therapy Clancy et al. (2015)79 Behavioral/Education Cognitive behavioral CBT 11 11 Unknown therapy Pöttgen et al. (2015)80 Behavioral/Education Cognitive behavioral CBT 27 27 Unknown therapy Wendebourg et al. (2014)81 Behavioral/Education Cognitive behavioral CBT (group) 16 16 Non-US therapy Mohr et al. (2007)82 Behavioral/Education Cognitive behavioral CBT (telephone) 127 62 US therapy Fischer et al. (2013)83 Behavioral/Education Cognitive behavioral Cognitive behavioral therapy (online) 90 45 Non-US therapy Vaughan et al. (2013)84 Behavioral/Education Cognitive training Alternating list and spatial memory tasks 29 10 Non-US Rilo et al. (2015)85 Behavioral/Education Cognitive training Cognitive rehabilitation (integrative, group based) 32 16 Non-US De Giglio et al. (2013)53 Behavioral/Education Cognitive training Cognitive training (home based video game) 35 18 Non-US Hildebrandt et al. (2007)86 Behavioral/Education Cognitive training Cognitive training (home based) 42 17 Non-US Mattioli et al. (2012)87 Behavioral/Education Cognitive training Cognitive training (online) 11 5 Non-US Vaughan et al. (2013)84 Behavioral/Education Cognitive training Continuous verbal list learning 29 10 Non-US Catalan et al. (2011)88 Behavioral/Education Cognitive training Neurocognitive rehabilitation 20 20 Unknown Rosti-Otajarvi et al. (2013)54 Behavioral/Education Cognitive training Neuropsychological rehabilitation 102 60 Non-US Tesar et al. (2005)89 Behavioral/Education Cognitive training Neuropsychological training program 19 10 Non-US Rosti-Otajarvi et al. (2014)90 Behavioral/Education Cognitive training Neuropsychological training program 56 56 Non-US Pérez-Martín et al. (2017)41 Behavioral/Education Cognitive training Neuropsychological training program (computer 62 30 Non-US assisted) Pusswald et al. (2014)91 Behavioral/Education Cognitive training Neuropsychological training program (computer 40 20 Non-US based) Vaughan et al. (2013)84 Behavioral/Education Cognitive training Verbal list learning alternating with rest (pacing) 29 9 Non-US 64

Table 5. Data for Evidence Map 1 (Abstracts on Interventions for Fatigue in MS), contnued

Reference Intervention Type of Intervention Specific Intervention Total Number US or Category Patien Assigned Non-US ts in to This Study Study Treatment Group Mattioli et al. (2012)87 Behavioral/Education Education Counseling 11 6 Non-US Shinto et al. (2008)52 Behavioral/Education Education Education 45 15 US Feys et al. (2013)92 Behavioral/Education Education Education (1 day) 42 42 Non-US Heine et al. (2016)93 Behavioral/Education Education Education MS nurse 90 45 Non-US Cunningham et al. (2017)94 Behavioral/Education Education Group and individual lifestyle education delivered NR NR US by OT students Lutz et al. (2017)95 Behavioral/Education Education (on exercise) Education (on exercise) 14 8 Non-US Motl et al. (2017)56 Behavioral/Education Education (on exercise) Education (on exercise) 47 23 US Turner et al. (2016)28 Behavioral/Education Education (on exercise) Education (on exercise) 64 31 US Turner et al. (2016)28 Behavioral/Education Education (on exercise) Education (on exercise) 64 33 US Mäurer et al. (2015)96 Behavioral/Education Education (on exercise) Education (on exercise) 178 89 Non-US Pilutti et al. (2014)48 Behavioral/Education Education (on exercise) Education (on exercise) 82 41 US Verrall et al. (2012)97 Behavioral/Education Education (on exercise) Education (on exercise) 92 44 US Kersten et al. (2014)98 Behavioral/Education Education (on exercise) Education (on exercise) 15 15 Non-US D'Hooghe et al. (2015)99 Behavioral/Education Education (on exercise) Education (on exercise, online) 70 70 Non-US Blikman et al. (2017)37 Behavioral/Education Energy conservation Energy conservation management program 86 42 Non-US program Garcia et al. (2011)100 Behavioral/Education Energy conservation Energy conservation management program 23 13 Non-US program Mathiowetz et al. (2005)101 Behavioral/Education Energy conservation Energy conservation management program 169 78 US program Vanage et al. (2003)102 Behavioral/Education Energy conservation Energy conservation management program 37 37 US program Mathiowetz et al. (2001)103 Behavioral/Education Energy conservation Energy conservation management program 54 54 US program Sauter et al. (2008)104 Behavioral/Education Energy conservation Energy conservation management program 32 32 Non-US program Finlayson et al. (2005)105 Behavioral/Education Energy conservation Energy conservation management program 29 29 US program Thomas et al. (2013)49 Behavioral/Education FACETS (CBT + energy FACETS (CBT + energy conservation) 164 84 Non-US conservation) Jeanette et al. (2017)106 Behavioral/Education FACETS (CBT + energy FACETS (CBT + energy conservation) 11 11 Non-US conservation) Hugos et al. (2010)35 Behavioral/Education Fatigue management Fatigue management program 41 21 US program Kos et al. (2007)23 Behavioral/Education Fatigue management Fatigue management program 51 51 Non-US program 65 Table 5. Data for Evidence Map 1 (Abstracts on Interventions for Fatigue in MS), contnued

Reference Intervention Type of Intervention Specific Intervention Total Number US or Category Patien Assigned Non-US ts in to This Study Study Treatment Group Horvat et al. (2013)107 Behavioral/Education Fatigue management Fatigue management program 75 19 Non-US program Turpin et al. (2015)108 Behavioral/Education Fatigue management Fatigue management program 35 35 Non-US program Poettgen et al. (2015)109 Behavioral/Education Fatigue management Fatigue management program (online) 275 137 Non-US program Finlayson et al. (2011)34 Behavioral/Education Fatigue management Fatigue management program (teleconference) 190 94 US program Hoogerwerf et al. (2017)110 Behavioral/Education Mindfulness Cognitive therapy (mindfulness based) 59 59 Unknown Bogosian et al. (2015)47 Behavioral/Education Mindfulness Mindfulness (telehealth) 40 19 Non-US Blankespoor et al. (2017)111 Behavioral/Education Mindfulness Mindfulness based stress reduction 25 25 Non-US Nejati et al. (2016)112 Behavioral/Education Mindfulness Mindfulness based stress reduction (group) 24 12 Non-US Grossman et al. (2010)24 Behavioral/Education Mindfulness Mindfulness based therapy 150 76 Non-US Frontario et al. (2016)113 Behavioral/Education Mindfulness Mindfulness meditation (telehealth) 30 20 US Eyssen et al. (2013)73 Behavioral/Education Occupational therapy OT 269 113 Non-US Eyssen et al. (2013)73 Behavioral/Education Occupational therapy OT (client centered) 269 156 Non-US Dahmardeh et al. (2017)114 Behavioral/Education Orem's self-care model Orem's self-care model 88 44 Non-US Afrasiabifar et al. (2016)43 Behavioral/Education Orem's self-care model Orem's self-care model 63 32 Non-US Garcia et al. (2011)100 Behavioral/Education Peer support Peer support group 23 10 Non-US Mohr et al. (2003)65 Behavioral/Education Psychotherapy Group psychotherapy 71 26 US Dayapoglu et al. (2012)115 Behavioral/Education Relaxation Progressive muscle relaxation 32 32 Non-US Kos et al. (2016)116 Behavioral/Education Relaxation Relaxation 31 14 Non-US Nazari et al. (2015)57 Behavioral/Education Relaxation Relaxation 75 25 Non-US Sgoifo et al. (2015)117 Behavioral/Education Relaxation Relaxation 48 24 Non-US van Kessel et al. (2008)64 Behavioral/Education Relaxation Relaxation 72 37 Non-US Vazirinejad et al. (2016)58 Behavioral/Education Relaxation, psychological Psychological training, muscle relaxation 60 30 Non-US training Boosman et al. (2011)118 Behavioral/Education Self-management Educational program on balancing capacity and 43 43 Non-US program load in daily activities Anderson et al. (2017)119 Behavioral/Education Self-management Self-management program 21 21 Non-US program Mulligan et al. (2015)120 Behavioral/Education Self-management Self-management program 25 25 Non-US program Sahebalzamani et al. Behavioral/Education Self-management Self-management program 50 50 Non-US (2012)121 program

66 Table 5. Data for Evidence Map 1 (Abstracts on Interventions for Fatigue in MS), contnued

Reference Intervention Type of Intervention Specific Intervention Total Number US or Category Patien Assigned Non-US ts in to This Study Study Treatment Group Navipour et al. (2006)122 Behavioral/Education Self-management Self-management program 34 34 Non-US program Hugos et al. (2017)123 Behavioral/Education Self-management Self-management program (group) 40 20 Unknown program Kos et al. (2016)116 Behavioral/Education Self-management Self-management program (occupational therapy) 31 17 Non-US program van Kessel et al. (2016)124 Behavioral/Education Self-management Self-management program (online) 39 20 Non-US program Moss-Morris et al. (2012)36 Behavioral/Education Self-management Self-management program (online) 40 23 Non-US program Ghahari et al. (2010)30 Behavioral/Education Self-management Self-management program (online) 95 34 Non-US program Jongen et al. (2015)125 Behavioral/Education Self-management Self-management program (online) 56 56 Unknown program van et al. (2016)124 Behavioral/Education Self-management Self-management program (online) + email 39 19 Non-US program support Ehde et al. (2015)70 Behavioral/Education Self-management Self-management program (telephone) 163 75 US program Ehde et al. (2015)70 Behavioral/Education Self-management Self-management program (telephone) 163 88 US program Louie et al. (2015)126 Behavioral/Education Self-management Self-management program (weekly exercise + 23 12 Non-US program education) McGuire et al. (2015)127 Behavioral/Education Wellness program Psychoeducational wellness program 54 43 Unknown Hart et al. (2011)128 Behavioral/Education Wellness program Wellness program 65 65 Unknown Plow et al. (2009)129 Behavioral/Education Wellness program Wellness program (group) 50 25 US Wade et al. (2002)20 CAM Lofepramine, Lofepramine, L-phenylalanine, and intramuscular 138 69 Non-US L-phenylalanine, B-12 vitamin B-12 Corey-Bloom et al. CAM Cannabis Smoked cannabis 37 37 US (2012)130 Consroe et al. (1997)131 CAM Cannabis Smoked cannabis 53 53 US Nilsagard et al. (2006)132 CAM Cooling therapy Cooling therapy 43 43 Non-US Schwid et al. (2003)133 CAM Cooling therapy Cooling therapy 84 84 US Gossmann et al. (2013)134 CAM Cooling therapy Cooling therapy 31 31 Non-US Gonzales et al. (2017)135 CAM Cooling therapy Cooling therapy (garment) 18 18 Unknown Beenakker et al. (2001)136 CAM Cooling therapy Cooling therapy (garment) 10 10 Non-US Weinstock-Guttman et al. CAM Low fat diet + omega 3 Low fat diet with omega 3 fatty acid 31 16 US (2005)137 supplementation

67 Table 5. Data for Evidence Map 1 (Abstracts on Interventions for Fatigue in MS), contnued

Reference Intervention Type of Intervention Specific Intervention Total Number US or Category Patien Assigned Non-US ts in to This Study Study Treatment Group de Carvalho et al. (2012)29 CAM Magnetic field therapy Magnetic field therapy 50 50 Non-US Brichetto et al. (2010)138 CAM Magnetic field therapy Magnetic field therapy 42 42 Non-US Mostert et al. (2005)139 CAM Magnetic field therapy Magnetic field therapy 25 12 Unknown Lappin et al. (2003)140 CAM Magnetic field therapy Magnetic field therapy 117 117 US Piatkowski et al. (2009)32 CAM Magnetic field therapy Magnetic field therapy (BEMER) 41 20 Non-US Richards et al. (1997)141 CAM Magnetic field therapy Magnetic field therapy (Enermed) 30 15 US Torkildsen et al. (2012)50 CAM Omega 3 Omega 3 fatty acids 92 46 Non-US Leocani et al. (2014)142 CAM THC-CBD oromucosal THC-CBD oromucosal spray 43 43 Non-US spray Vermersch et al. (2016)143 CAM THC-CBD oromucosal THC-CBD oromucosal spray 433 433 Non-US spray Gilbertson et al. (2017)144 Combination Exercise, mindfulness Yoga, mindfulness meditation, relaxing music 22 22 Unknown Catena et al. (2014)145 Combination Exercise, relaxation Aerobic and respiratory exercises +Muscle 20 10 Non-US relaxation techniques Abolhasani et al. (2016)146 Combination Exercise, special diet Exercise + Mediterranean diet 70 35 Non-US Lee et al. (2017)147 Combination Exercise, special diet Exercise + paleo diet + neuromuscular electrical 19 19 US stimulation Bisht et al. (2014)148 Combination Exercise, special diet, Exercise, electrical stimulation, meditation, 10 10 US meditation massage, paleolithic diet Leocani et al. (2012)149 Combination Rehabilitation, rTMS Inpatient rehabilitation + rTMS 23 11 Non-US Schmidt et al. (2014)150 Exercise Aerobic exercise Aerobic endurance exercise 89 89 Non-US Mokhtarzade et al. (2017)40 Exercise Aerobic exercise Aerobic exercise 45 25 Non-US Hasanpour et al. (2016)59 Exercise Aerobic exercise Aerobic exercise 90 30 Non-US Heine et al. (2016)93 Exercise Aerobic exercise Aerobic exercise 90 45 Non-US Petajan et al. (1996)18 Exercise Aerobic exercise Aerobic exercise 54 21 US Kara et al. (2017)151 Exercise Aerobic exercise Aerobic exercise 35 21 Non-US Hassanpour-Dehkordi et al. Exercise Aerobic exercise Aerobic exercise 90 20 Unknown (2014)152 Rasova et al. (2006)153 Exercise Aerobic exercise Aerobic exercise 112 24 Non-US Tellez et al. (2013)154 Exercise Aerobic exercise Aerobic exercise 14 14 Non-US Samaei et al. (2016)155 Exercise Aerobic exercise Treadmill (downhill) 34 17 Unknown Ensari et al. (2017)156 Exercise Aerobic exercise Treadmill (high intensity) 24 24 Unknown Ensari et al. (2017)156 Exercise Aerobic exercise Treadmill (light intensity) 24 24 Unknown Ensari et al. (2017)156 Exercise Aerobic exercise Treadmill (medium intensity) 24 24 Unknown Samaei et al. (2016)155 Exercise Aerobic exercise Treadmill (uphill) 34 17 Unknown Gervasoni et al. (2014)157 Exercise Aerobic exercise Treadmill exercise 30 15 Unknown 68 Table 5. Data for Evidence Map 1 (Abstracts on Interventions for Fatigue in MS), contnued

Reference Intervention Type of Intervention Specific Intervention Total Number US or Category Patien Assigned Non-US ts in to This Study Study Treatment Group Ahmadi et al. (2013)158 Exercise Aerobic exercise Treadmill exercise 31 10 Non-US van den Berg et al. Exercise Aerobic exercise Treadmill exercise 19 19 Non-US (2006)159 Spain et al. (2016)160 Exercise Aerobic exercise Treadmill exercise 11 11 US Newman et al. (2007)161 Exercise Aerobic exercise Treadmill exercise 16 16 Non-US Pilutti et al. (2016)162 Exercise Aerobic exercise Treadmill exercise (body weight supported), 12 6 US recumbent stepping Kargarfard et al. (2017)42 Exercise Aquatic exercise Aquatic exercise 32 17 Non-US Razazian et al. (2016)61 Exercise Aquatic exercise Aquatic exercise 54 18 Non-US Kooshiar et al. (2015)25 Exercise Aquatic exercise Aquatic exercise 37 18 Non-US Kargarfard et al. (2012)163 Exercise Aquatic exercise Aquatic exercise 32 16 Non-US Bansi et al. (2013)164 Exercise Aquatic exercise Aquatic exercise (bike) 60 30 Non-US Irkec et al. (2013)165 Exercise Aquatic exercise Aquatic therapy (Ai chi) 18 11 Non-US Bayraktar et al. (2013)166 Exercise Aquatic exercise Aquatic therapy (Ai chi) 23 15 Non-US Guclu-Gunduz et al. Exercise Aquatic exercise Aquatic therapy (Ai chi) 29 11 Non-US (2013)167 Kasser et al. (2015)168 Exercise Balance training Balance training 10 10 US Frevel et al. (2015)169 Exercise Balance training Balance training (home based) 18 9 Non-US Gandolfi et al. (2015)170 Exercise Balance training Balance training (sensory integration) 80 39 Non-US Gandolfi et al. (2014)67 Exercise Balance training Balance training (sensory integration) 22 10 Non-US Brichetto et al. (2013)171 Exercise Balance training Balance training (standard) 36 18 Non-US Brichetto et al. (2013)171 Exercise Balance training Balance training (Wii) 36 18 Non-US Dettmers et al. (2009)172 Exercise Balance training Balance training, stretching, coordination training 30 15 Non-US Kerling et al. (2015)71 Exercise Endurance exercise Endurance exercise 37 19 Non-US Skjerbaek et al. (2013)173 Exercise Endurance exercise Endurance exercise 16 16 Non-US Sabapathy et al. (2011)174 Exercise Endurance exercise Endurance exercise 21 21 Non-US Dettmers et al. (2009)172 Exercise Endurance exercise Endurance exercise 30 15 Non-US Bansi et al. (2013)164 Exercise Endurance exercise Endurance training (cycle ergometry) 60 30 Non-US Negahban et al. (2013)175 Exercise Exercise Exercise 48 12 Non-US Hayes et al. (2011)176 Exercise Exercise Exercise 22 11 US McCullagh et al. (2008)177 Exercise Exercise Exercise 30 17 Non-US Keser et al. (2011)178 Exercise Exercise Exercise 30 15 Non-US Learmonth et al. (2011)179 Exercise Exercise Exercise (group based community) 32 20 Non-US Aydin et al. (2014)72 Exercise Exercise Exercise (home based) 40 20 Non-US Geddes et al. (2009)180 Exercise Exercise Exercise (home based) 15 9 US 69 Table 5. Data for Evidence Map 1 (Abstracts on Interventions for Fatigue in MS), contnued

Reference Intervention Type of Intervention Specific Intervention Total Number US or Category Patien Assigned Non-US ts in to This Study Study Treatment Group Aydin et al. (2014)72 Exercise Exercise Exercise (hospital based) 40 16 Non-US Küçük et al. (2016)181 Exercise Exercise Exercise (traditional) 20 9 Unknown Oken et al. (2004)60 Exercise Exercise Exercise class 69 21 US Mostert et al. (2002)182 Exercise Exercise Exercise program 26 13 Unknown Smith et al. (2009)183 Exercise Exercise Exercise program 10 10 Non-US Fjeldstad et al. (2016)184 Exercise Exercise Exercise program (home based) 30 10 US ErtekIn et al. (2012)185 Exercise Exercise Exercise program (home based) 40 40 Non-US Fjeldstad et al. (2016)184 Exercise Exercise Exercise program (home based) + 30 10 US In Person PT Fjeldstad et al. (2016)184 Exercise Exercise Exercise program (home based) + 30 10 US Remote PT supervision Vore et al. (2011)186 Exercise Exercise Exercise program (individual) 13 13 Unknown Smith et al. (2006)187 Exercise Exercise Exercise session (single) 34 34 Non-US Irkec et al. (2013)165 Exercise Exercise (other) Abdominal breathing and extremity exercises 18 7 Non-US Rasova et al. (2006)153 Exercise Exercise (other) Aerobic + neurophysiologically based 112 36 Non-US physiotherapy Konecný et al. (2010)188 Exercise Exercise (other) Aerobic + resistance training 15 15 Non-US Bayraktar et al. (2013)166 Exercise Exercise (other) Arm and leg exercises + abdominal breathing 23 8 Non-US Briken et al. (2012)189 Exercise Exercise (other) Arm ergometry 47 12 Non-US Briken et al. (2012)189 Exercise Exercise (other) Bicycle ergometry 47 12 Non-US Straudi et al. (2014)190 Exercise Exercise (other) Circuit training 24 12 Non-US Novotna et al. (2015)191 Exercise Exercise (other) Circuit training (aerobic + resistance) 50 24 Non-US Novotna et al. (2015)191 Exercise Exercise (other) Circuit training (resistance) 50 26 Non-US Karpatkin et al. (2015)192 Exercise Exercise (other) Continuous exercise 27 27 US Bernhardt et al. (2012)193 Exercise Exercise (other) Core stability training 70 23 Unknown Lopes et al. (2011)194 Exercise Exercise (other) Cycle ergometry 57 57 Non-US Huisinga et al. (2011)195 Exercise Exercise (other) Elliptical exercise 26 26 US Kerling et al. (2015)71 Exercise Exercise (other) Endurance +resistance exercise (bicycle 37 18 Non-US ergometry) Sangelaji et al. (2014)45 Exercise Exercise (other) Exercise therapy (aerobic, strengthening, 59 39 Non-US balancing and stretching exercises) Bernhardt et al. (2011)196 Exercise Exercise (other) Gymnastic training 49 24 Non-US Klefbeck et al. (2003)197 Exercise Exercise (other) Inspiratory muscle training 15 7 Non-US Karpatkin et al. (2015)192 Exercise Exercise (other) Intermittent exercise 27 27 US Siengsukon et al. (2016)198 Exercise Exercise (other) Low intensity walking and stretching program 28 14 US

70 Table 5. Data for Evidence Map 1 (Abstracts on Interventions for Fatigue in MS), contnued

Reference Intervention Type of Intervention Specific Intervention Total Number US or Category Patien Assigned Non-US ts in to This Study Study Treatment Group Colamarino et al. (2012)199 Exercise Exercise (other) Rehabilitation (bicycle ergometry) 25 25 Unknown Ray et al. (2013)200 Exercise Exercise (other) Respiratory muscle training (inspiratory and 21 21 US expiratory) Fisher et al. (2014)201 Exercise Exercise (other) Respiratory muscle training (resistance) 17 9 US Briken et al. (2012)189 Exercise Exercise (other) Rowing 47 12 Non-US Velikonja et al. (2010)202 Exercise Exercise (other) Sports climbing 20 10 Non-US Burschka et al. (2014)203 Exercise Exercise (other) Tai Chi 32 15 Non-US Pilutti et al. (2016)162 Exercise Exercise (other) Total body recumbent stepper training 12 6 US Carter et al. (2013)44 Exercise Exercise (supervised) Aerobic exercise, strength and balance training 120 60 Non-US (supervised) Tallner et al. (2012)204 Exercise Exercise (supervised) Exercise (supervised online) 126 63 Non-US Siengsukon et al. (2016)198 Exercise Exercise (supervised) Exercise (supervised) 28 14 US Tarakci et al. (2013)27 Exercise Exercise (supervised) Exercise (supervised) 99 51 Non-US Surakka et al. (2004)205 Exercise Exercise (supervised) Exercise (supervised) 95 47 Non-US Garrett et al. (2013)62 Exercise Exercise (supervised) Exercise (supervised, fitness instructor) 314 86 Non-US Garrett et al. (2013)62 Exercise Exercise (supervised) Exercise (supervised, physiotherapist) 314 80 Non-US Thomas et al. (2017)206 Exercise Exercise (supervised) Wii intervention (supervised) 30 30 Non-US Pompa et al. (2017)207 Exercise Gait training (robot Gait training (robot assisted) 50 25 Non-US assisted) Straudi et al. (2016)68 Exercise Gait training (robot Gait training (robot assisted) 58 30 Non-US assisted) Gandolfi et al. (2014)67 Exercise Gait training (robot Gait training (robot assisted) 22 12 Non-US assisted) Venturi et al. (2014)208 Exercise Gait training (robot Gait training (robot assisted) 40 20 Non-US assisted) Venturini et al. (2011)209 Exercise Gait training (robot Gait training (robot assisted) 20 10 Non-US assisted) Kalron et al. (2016)69 Exercise Physical therapy Physical therapy 45 23 Non-US Straudi et al. (2016)68 Exercise Physical therapy Physical therapy 58 28 Non-US Gandolfi et al. (2015)170 Exercise Physical therapy Physical therapy 80 41 Non-US Brichetto et al. (2011)210 Exercise Physical therapy Physical therapy 20 10 Non-US Venturini et al. (2011)209 Exercise Physical therapy Physical therapy 20 10 Non-US Rasova et al. (2006)153 Exercise Physical therapy Physical therapy 112 19 Non-US Brichetto et al. (2013)211 Exercise Physical therapy Physical therapy 209 209 Non-US Plow et al. (2009)129 Exercise Physical therapy Physical therapy (individual) 50 25 US Seebacher et al. (2017)212 Exercise Physical therapy Physical therapy (motor imagery) 112 38 Non-US 71 Table 5. Data for Evidence Map 1 (Abstracts on Interventions for Fatigue in MS), contnued

Reference Intervention Type of Intervention Specific Intervention Total Number US or Category Patien Assigned Non-US ts in to This Study Study Treatment Group Seebacher et al. (2017)212 Exercise Physical therapy Physical therapy (verbal cuing) 112 36 Non-US Küçük et al. (2016)181 Exercise Pilates Pilates 20 11 Unknown Kalron et al. (2016)69 Exercise Pilates Pilates 45 22 Non-US Catena et al. (2014)145 Exercise Pilates Pilates 20 10 Non-US Kara et al. (2017)151 Exercise Pilates Pilates 35 9 Non-US Guclu-Gunduz et al. Exercise Pilates Pilates 29 18 Non-US (2013)167 Soysal et al. (2016)213 Exercise Pilates Pilates 11 11 Non-US Bulguroglu et al. (2015)214 Exercise Pilates Pilates (Mat) 38 12 Non-US Bulguroglu et al. (2015)214 Exercise Pilates Pilates (Reformer) 38 13 Non-US Rietberg et al. (2014)26 Exercise Rehabilitation Multidisciplinary rehabilitation 48 23 Non-US Studer et al. (2017)215 Exercise Rehabilitation Multidisciplinary rehabilitation (inpatient) 30 30 Non-US Keser et al. (2011)178 Exercise Rehabilitation Neurorehabilitation 30 15 Non-US Brichetto et al. (2010)216 Exercise Rehabilitation Rehabilitation (Wii balance board) 36 18 Non-US Bergsland et al. (2015)217 Exercise Rehabilitation Rehabilitation 29 29 Non-US Brichetto et al. (2015)218 Exercise Rehabilitation Rehabilitation (conventional) 32 16 Non-US Brichetto et al. (2015)218 Exercise Rehabilitation Rehabilitation (individualized) 32 16 Non-US Skjerbæk et al. (2013)219 Exercise Rehabilitation Rehabilitation (inpatient) 11 5 Non-US Skjerbæk et al. (2013)219 Exercise Rehabilitation Rehabilitation (inpatient) + exercise therapy 11 6 Non-US Patti et al. (2002)220 Exercise Rehabilitation Rehabilitation (outpatient) 111 58 Non-US Rasova et al. (2005)221 Exercise Rehabilitation Rehabilitation (outpatient) 28 17 Non-US Di Fabio et al. (1998)222 Exercise Rehabilitation Rehabilitation (outpatient) 46 20 US Brichetto et al. (2010)216 Exercise Rehabilitation Rehabilitation (standard) 36 18 Non-US Pasiut et al. (2015)223 Exercise Rehabilitation Rehabilitation program 32 32 Non-US Niwald et al. (2017)224 Exercise Rehabilitation Rehabilitation program (aerobic focused) 53 21 Non-US Niwald et al. (2017)224 Exercise Rehabilitation Rehabilitation program (non-aerobic) 53 32 Non-US Nedeljkovic et al. (2014)31 Exercise Rehabilitation Rehabilitation program + high dose 39 19 Non-US methylprednisolone Venturi et al. (2014)208 Exercise Rehabilitation Rehabilitation program (conventional) 40 20 Non-US Egner et al. (2003)225 Exercise Rehabilitation Telephone rehabilitation 27 11 US Egner et al. (2003)225 Exercise Rehabilitation Video telerehabilitation 27 9 US Vikman et al. (2008)226 Exercise Rehabilitation Inpatient rehabilitation 58 58 Non-US Drulovic et al. (2013)227 Exercise Rehabilitation Inpatient rehabilitation 151 151 Non-US Romberg et al. (2008)228 Exercise Rehabilitation Inpatient rehabilitation 91 91 Non-US Leocani et al. (2012)149 Exercise Rehabilitation Inpatient rehabilitation 23 11 Non-US 72 Table 5. Data for Evidence Map 1 (Abstracts on Interventions for Fatigue in MS), contnued

Reference Intervention Type of Intervention Specific Intervention Total Number US or Category Patien Assigned Non-US ts in to This Study Study Treatment Group Storr et al. (2006)229 Exercise Rehabilitation Inpatient rehabilitation (multidisciplinary) 90 38 Non-US Moradi et al. (2015)230 Exercise Resistance training Progressive resistance training 20 10 Non-US Coote et al. (2015)231 Exercise Resistance training Progressive resistance training 37 18 Non-US Dalgas et al. (2010)33 Exercise Resistance training Progressive resistance training 31 16 Non-US Cakt et al. (2010)232 Exercise Resistance training Progressive resistance training (cycling) 45 30 Non-US Dodd et al. (2011)51 Exercise Resistance training Progressive resistance training (gymnastics 71 36 Non-US based) Skjerbaek et al. (2013)173 Exercise Resistance training Resistance exercise 16 16 Non-US Sabapathy et al. (2011)174 Exercise Resistance training Resistance exercise 21 21 Non-US Hayes et al. (2011)176 Exercise Resistance training Resistance exercise via negative eccentrically 22 11 US induced work (RENEW) White et al. (2006)233 Exercise Resistance training Resistance training 12 12 US Kierkegaard et al. (2016)234 Exercise Resistance training Resistance training (high intensity) 20 20 Non-US Manca et al. (2013)235 Exercise Resistance training Resistance training (high intensity) NR NR Non-US Bernhardt et al. (2012)193 Exercise Resistance training Resistance training (progressive) 70 24 Unknown Manca et al. (2017)236 Exercise Strength training Strength training 30 15 Non-US Manca et al. (2017)236 Exercise Strength training Strength training 30 15 Non-US Hebert et al. (2016)237 Exercise Vestibular rehabilitation Vestibular rehabilitation 88 44 US Hebert et al. (2011)238 Exercise Vestibular rehabilitation Vestibular rehabilitation 38 12 US Nejati et al. (2016)112 Exercise Yoga Yoga 24 12 Non-US Razazian et al. (2016)61 Exercise Yoga Yoga 54 18 Non-US Hasanpour et al. (2016)59 Exercise Yoga Yoga 90 30 Non-US Ahmadi et al. (2013)158 Exercise Yoga Yoga 31 11 Non-US Garrett et al. (2013)62 Exercise Yoga Yoga 314 77 Non-US Velikonja et al. (2010)202 Exercise Yoga Yoga 20 10 Non-US Oken et al. (2004)60 Exercise Yoga Yoga 69 26 US Tacchino et al. (2017)239 Exercise Yoga Yoga 20 10 Non-US Hassanpour-Dehkordi et al. Exercise Yoga Yoga 90 20 Unknown (2014)152 Cohen et al. (2017)240 Exercise Yoga Yoga 14 14 Unknown Karbandi et al. (2015)241 Exercise Yoga Yoga (group) 85 44 Non-US Karbandi et al. (2015)241 Exercise Yoga Yoga (individual) 85 41 Non-US Nuara et al. (2016)242 Other rTMS rTMS 42 21 Non-US Schippling et al. (2014)243 Other rTMS rTMS 28 19 Non-US Gaede et al. (2012)244 Other rTMS rTMS 26 26 Non-US 73 Table 5. Data for Evidence Map 1 (Abstracts on Interventions for Fatigue in MS), contnued

Reference Intervention Type of Intervention Specific Intervention Total Number US or Category Patien Assigned Non-US ts in to This Study Study Treatment Group Todorov et al. (2016)245 Other rTMS rTMS 35 35 Non-US Mori et al. (2011)246 Other rTMS rTMS 30 10 Non-US Hanken et al. (2016)247 Other tDCS Transcranial direct current stimulation (tDCS) 52 35 Non-US Charvet et al. (2017)248 Other tDCS Transcranial direct current stimulation (remotely 20 10 US supervised) Chalah et al. (2017)249 Other tDCS Transcranial direct current stimulation (tDCS) 10 10 Non-US Ayache et al. (2016)250 Other tDCS Transcranial direct current stimulation (tDCS) 16 16 Non-US Tecchio et al. (2015)251 Other tDCS Transcranial direct current stimulation (tDCS) 21 21 Unknown Tecchio et al. (2014)252 Other tDCS Transcranial direct current stimulation (tDCS) 10 10 Unknown Ferrucci et al. (2014)253 Other tDCS Transcranial direct current stimulation (tDCS) 25 25 Non-US Vannorsdall et al. (2015)254 Other tDCS Transcranial direct current stimulation (tDCS) NR NR US Saiote et al. (2014)255 Other tDCS Transcranial direct current stimulation (tDCS) NR NR Non-US Chan et al. (2017)256 Other tDCS Transcranial direct current stimulation (tDCS), 25 25 US remotely supervised Polman et al. (1994)257 Pharmacologic 3, 4 diaminopyridine 3, 4 diaminopyridine 10 10 Non-US De et al. (2017)258 Pharmacologic 4'aminopyridine 4'aminopyridine 120 80 Non-US Jacques et al. (2016)259 Pharmacologic 4'aminopyridine 4'aminopyridine 37 18 Non-US Simpson et al. (2016)260 Pharmacologic 4'aminopyridine 4'aminopyridine 40 20 Non-US Drake et al. (2016)261 Pharmacologic 4'aminopyridine 4'aminopyridine 61 30 US Goodman et al. (2007)262 Pharmacologic 4'aminopyridine 4'aminopyridine 36 25 US Romani et al. (2004)63 Pharmacologic 4'aminopyridine 4'aminopyridine 40 20 Non-US Rossini et al. (2001)19 Pharmacologic 4'aminopyridine 4'aminopyridine 54 54 Non-US Polman et al. (1994)257 Pharmacologic 4'aminopyridine 4'aminopyridine 10 10 Non-US Barros et al. (2016)263 Pharmacologic 4'aminopyridine 4'aminopyridine 20 20 Non-US Kurtuncu et al. (2016)264 Pharmacologic 4'aminopyridine 4'aminopyridine 179 179 Non-US Baruca et al. (2015)265 Pharmacologic 4'aminopyridine 4'aminopyridine 30 30 Non-US Prugger et al. (2012)266 Pharmacologic 4'aminopyridine 4'aminopyridine 67 67 Non-US Morrow et al. (2017)267 Pharmacologic 4'aminopyridine 4'aminopyridine 60 60 Non-US Korsen et al. (2017)268 Pharmacologic 4'aminopyridine 4'aminopyridine (dalfampridine) 24 24 Non-US Triche et al. (2016)269 Pharmacologic 4'aminopyridine 4'aminopyridine (dalfampridine) 39 39 US Ruck et al. (2014)270 Pharmacologic 4'aminopyridine 4'aminopyridine (dalfampridine) 52 52 Non-US Guyot et al. (2014)271 Pharmacologic 4'aminopyridine 4'aminopyridine (dalfampridine) 134 134 Non-US Weller et al. (2013)272 Pharmacologic 4'aminopyridine 4'aminopyridine (fampridine) 61 61 Non-US Broicher et al. (2014)273 Pharmacologic 4'aminopyridine 4'aminopyridine (fampridine) 32 32 Non-US Benoît et al. (2014)274 Pharmacologic 4'aminopyridine 4'aminopyridine (fampridine) 111 111 Non-US 74 Table 5. Data for Evidence Map 1 (Abstracts on Interventions for Fatigue in MS), contnued

Reference Intervention Type of Intervention Specific Intervention Total Number US or Category Patien Assigned Non-US ts in to This Study Study Treatment Group Farrell et al. (2014)275 Pharmacologic 4'aminopyridine 4'aminopyridine (fampridine) 137 137 Non-US Sobek et al. (2012)276 Pharmacologic 4'aminopyridine 4'aminopyridine (fampridine) 117 117 Non-US Sagawa et al. (2016)277 Pharmacologic 4'aminopyridine 4'aminoypyridine (fampridine) 50 50 Unknown Allart et al. (2015)278 Pharmacologic 4'aminopyridine 4'aminoypyridine (fampridine) 120 120 Non-US Ledinek et al. (2014)279 Pharmacologic Amantidine Amantidine 60 15 Non-US Shaygannejad et al. Pharmacologic Amantidine Amantidine 52 52 Unknown (2012)280 Ashtari et al. (2009)281 Pharmacologic Amantidine Amantidine 42 21 Non-US Tomassini et al. (2004)66 Pharmacologic Amantidine Amantidine 36 36 Non-US Krupp et al. (1995)21 Pharmacologic Amantidine Amantidine 93 39 US Rosenberg et al. (1988)282 Pharmacologic Amantidine Amantidine 10 10 US Canadian Multiple Sclerosis Pharmacologic Amantidine Amantidine 115 115 Non-US Research Group (1987)283 Horvat et al. (2013)107 Pharmacologic Amantidine Amantidine 75 19 Non-US Geisler et al. (1996)284 Pharmacologic Amantidine Amantidine 45 45 US Cohen et al. (1989)285 Pharmacologic Amantidine Amantidine 29 29 US Thaera et al. (2012)286 Pharmacologic Amantidine Amantidine 22 22 US Moghaddam et al. (2013)287 Pharmacologic Amantidine, aspirin Amantidine + aspirin 45 23 Non-US Bruce et al. (2012)288 Pharmacologic Armodafinil Armodafinil 33 33 US Sadeghi-Naini et al. Pharmacologic Aspirin Aspirin 121 61 Non-US (2017)39 Shaygannejad et al. Pharmacologic Aspirin Aspirin 52 52 Unknown (2012)280 Wingerchuk et al. (2005)289 Pharmacologic Aspirin Aspirin 30 30 US Wingerchuk et al. (2014)290 Pharmacologic Aspirin Aspirin (high and low dose) 60 60 US Bayas et al. (2016)291 Pharmacologic Citalopram Citalopram 54 54 Non-US Solaro et al. (2013)292 Pharmacologic Duloxetine Duloxetine 63 63 Non-US Romani et al. (2004)63 Pharmacologic Fluoxetine Fluoxetine 40 20 Non-US Bayas et al. (2016)291 Pharmacologic Fluoxetine Fluoxetine 54 54 Non-US Gillson et al. (1999)293 Pharmacologic Histamine Histamine cream 55 55 Non-US Gillson et al. (2002)294 Pharmacologic Histamine, caffeine Histamine and caffeine 29 22 Non-US Horvat et al. (2013)107 Pharmacologic L-carnitine L carnitine 75 18 Non-US Ouallet et al. (2014)295 Pharmacologic L-carnitine L-carnitine 59 59 Non-US Ledinek et al. (2014)279 Pharmacologic L-carnitine L-carnitine 60 15 Non-US Tomassini et al. (2004)66 Pharmacologic L-carnitine L-carnitine 36 36 Non-US

75 Table 5. Data for Evidence Map 1 (Abstracts on Interventions for Fatigue in MS), contnued

Reference Intervention Type of Intervention Specific Intervention Total Number US or Category Patien Assigned Non-US ts in to This Study Study Treatment Group Lebrun et al. (2006)296 Pharmacologic L-carnitine L-carnitine 170 170 Non-US Cameron et al. (2017)297 Pharmacologic Methylphenidate Methylphenidate 24 12 US Ford-Johnson et al. Pharmacologic Modafinil Modafinil 17 17 US (2016)298 Ledinek et al. (2014)279 Pharmacologic Modafinil Modafinil 60 15 Non-US Szabadi et al. (2011)299 Pharmacologic Modafinil Modafinil 26 26 Non-US Moller et al. (2011)55 Pharmacologic Modafinil Modafinil 121 62 Non-US Lange et al. (2009)300 Pharmacologic Modafinil Modafinil 21 12 Non-US Stankoff et al. (2005)301 Pharmacologic Modafinil Modafinil 115 56 Non-US Horvat et al. (2013)107 Pharmacologic Modafinil Modafinil 75 18 Non-US Rammohan et al. (2002)302 Pharmacologic Modafinil Modafinil 72 72 US Littleton et al. (2010)303 Pharmacologic Modafinil Modafinil 39 39 Non-US Zifko et al. (2002)304 Pharmacologic Modafinil Modafinil 50 50 Non-US Ehde et al. (2008)22 Pharmacologic Paroxetine Paroxetine 42 22 US Mohr et al. (2003)65 Pharmacologic Sertraline Sertraline 71 22 US Bayas et al. (2016)291 Pharmacologic Venlafaxine Venlafaxine 54 54 Non-US Note: In some cases, the number of patients per treatment arm was not reported (i.e., for certain conference abstracts); in such cases, number of patients per treatment arm was estimated based on total number of patients in the study and number of treatment arms.

Table 6. Fatigue And Quality of Life Data for Evidence Map 2: Pharmacologic Interventions Trial Group 1 Group 2 Hedges' g Outcome Single Group 1 Group 1 Group 2 Group 2 Outcome Specific Specific (95% CI) (Instrument) Study Baseline Outcome Mean Baseline Mean (SD) (N at Treatment Inactive Finding Mean (SD) (SD) (N at Mean (SD) Follow-up) Treatment Follow-up) Rossini 4-AP Placebo 0.38 Fatigue (FSS) Inconclusive 5.32 4.64 4.9 4.61 (2001)19 (-0.19 to 0.95) (SD: NR) (SD:NR) (N=27) (SD: NR) (SD:NR) (N=22) Krupp (1995)21 Amantadine Placebo 0.2 Fatigue (FSS) Inconclusive 5.61 5.16 5.63 5.4 (-0.28 to 0.69) (SD: 0.95) (SD:1.22) (N=31) (SD: 0.89) (SD:1.18) (N=35) Krupp (1995)21 Amantadine Placebo 0.41 Fatigue (MS-FS) Inconclusive 4.9 4.4 4.69 4.72 (-0.08 to 0.9) (SD: 1.225) (SD:1.67) (N=31) (SD: 0.947) (SD:1.183) (N=35) Sadeghi-Naini Aspirin Placebo 0.06 Fatigue (FSS) Inconclusive 37.2 31 41 37.4 (2017)39 (-0.33 to 0.45) (SD: NR) (SD:NR) (N=51) (SD: NR) (SD:NR) (N=49) Sadeghi-Naini Aspirin Placebo 0.04 Fatigue (MFIS total) Inconclusive 38.6 32 42.7 37.5 (2017)39 (-0.35 to 0.43) (SD: NR) (SD:NR) (N=51) (SD: NR) (SD:NR) (N=49) Moller (2011)55 Modafinil Placebo 0.38 Fatigue (FSS) Favors 6.01 5.25 5.8 5.42 (0 to 0.76) Modafinil (SD: 0.75) (SD:1.24) (N=55) (SD: 0.76) (SD:1) (N=55) Moller (2011)55 Modafinil Placebo 0.18 Fatigue (MFIS) Inconclusive 54.75 45.3 51.2 44.3 (-0.2 to 0.55) (SD: 13.32) (SD:16.3) (N=55) (SD: 11.8) (SD:15.2) (N=55) Moller (2011)55 Modafinil Placebo -0.08 QOL (Hamburg Inconclusive 12.1 11.49 11.86 11.04 (-0.45 to 0.3) QOL Questionnaire (SD: 2.44) (SD:3.29) (N=55) (SD: 2.52) (SD:2.52) (N=55) in MS [higher scores are WORSE]) Ehde (2008)22 Paroxetine No treatment 0.84 Fatigue (MFIS) Favors 57.2 39.3 56.7 52.1 (0.17 to 1.51) paroxetine (SD: 14.1) (SD:14.8) (N=17) (SD: 12.6) (SD:18.3) (N=19) Ehde (2008)22 Paroxetine No treatment -0.3 QOL (SF-36 Inconclusive 40.8 36.4 36 35.5 (-0.95 to 0.35) physical functioning) (SD: 13.2) (SD:12.3) (N=17) (SD: 11.4) (SD:13.3) (N=18) FSS- Fatigue Severity Scale MFIS – Modified Fatidue Impact Scale NR – Not reported QOL – Quality of life SD – Standard deviation

Table 7. Fatigue And Quality of Life Data for Evidence Map 2: Exercise Interventions Trial Group 1 Group 2 Hedges' g Outcome Single Study Group 1 Group 1 Group 2 Group 2 Comments Specific Specific (95% CI) (Instrument) Finding Baseline Outcome Baseline Outcome Treatment Inactive Mean (SD) Mean (SD) Mean (SD) Mean (SD) Treatment (N at (N at Follow-up) Follow-up) Kooshiar Aquatic therapy Usual care 0.65 Fatigue (FSS) Favors 41.75 36.06 38.33 39.14 (2015)25 (0.01 to 1.3) aquatic (SD: 8.33) (SD:12.2) (SD: 9.01) (SD:8.1) exercise (N=18) (N=19) Razazian Aquatic exercise Usual care 1.9 Fatigue (FSS) Favors 48.72 25.28 39.56 41.22 (2016)61 (1.12 to 2.67) aquatic (SD: 11.46) (SD:11.71) (SD: 14.68) (SD:13.52) exercise (N=18) (N=18) Kooshiar Aquatic therapy Usual care 0.84 Fatigue (MFIS) Favors 43.81 32.56 41.29 42 (2015)25 (0.18 to 1.5) aquatic (SD: 14.87) (SD:16.07) (SD: 12.53) (SD:12.15) exercise (N=18) (N=19) Kargarfard Aquatic exercise Usual care 2.36 Fatigue (MFIS) Favors 43.1 32.8 44.5 61 (2017)42 (1.47 to 3.25) aquatic (SD: 14.6) (SD:5.9) (SD: 9.3) (SD:8.2) exercise (N=17) (N=15) Kooshiar Aquatic therapy Usual care 1.47 QOL Favors 63.13 80.06 65.48 66.52 (2015)25 (0.76 to 2.19) (Multicultural aquatic (SD: 13.02) (SD:11.53) (SD: 9.74) (SD:6.22) Quality of Life exercise (N=18) (N=19) Index (MQLIM)) Tarakci Group exercise Monthly 1.41 Fatigue (FSS) Favors group 39.27 31.01 39.84 43.13 (2013)27 led by physical phone call (0.97 to 1.85) exercise led (SD: 7.19) (SD:7.24) (SD: 8.44) (SD:9.66) therapist from a by physical (N=51) (N=48) neurologist therapist Garrett Exercise led by No treatment 0.47 Fatigue (MFIS Favors Used (2013)62 physiotherapist (0.14 to 0.8) total) supervised (SD: NR) (SD:NR) (SD: NR) (SD:NR) reported or fitness exercise (N=63) (N=67) CIs of instructor individual group change scores to calculate Hedges' g Oken Exercise Waitlist 0.24 Fatigue (Multi- Inconclusive 13.2 12.1 15.2 14.9 (2004)60 stationery bike (-0.43 to 0.91) dimensional (SD: 4) (SD:2.8) (SD: 3.4) (SD:3) Fatigue Inventory (N=15) (N=20) [MFI])

Table 7. Fatigue And Quality of Life Data for Evidence Map 2: Exercise Interventions, continued

Trial Group 1 Group 2 Hedges' g Outcome Single Study Group 1 Group 1 Group 2 Group 2 Comments Specific Specific (95% CI) (Instrument) Finding Baseline Outcome Baseline Outcome Treatment Inactive Mean (SD) Mean (SD) Mean (SD) Mean (SD) Treatment (N at (N at Follow-up) Follow-up) Garrett Exercise led by No treatment 0.46 QOL (MSIS-29 Favors Used (2013)62 physiotherapist (0.13 to 0.79) Physical [higher supervised (SD: NR) (SD:NR) (SD: NR) (SD:NR) reported or fitness scores are exercise (N=67) (N=49) CIs of instructor WORSE]) individual group change scores to calculate Hedges' g Tarakci Group exercise Monthly 0.25 QOL (MusiQOL) Inconclusive 74.41 76.39 73.42 73.02 (2013)27 led by physical phone call (-0.15 to 0.64) (SD: 9.2) (SD:9.53) (SD: 9.73) (SD:10.3) therapist from a (N=51) (N=48) neurologist Oken Exercise Waitlist -0.08 QOL (SF-36 Inconclusive 62 60 58.1 58.1 (2004)60 stationery bike (-0.75 to 0.59) physical (SD: 25.9) (SD:27.9) (SD: 19) (SD:23.3) functioning) (N=15) (N=20) Petajan Exercise No treatment NR Fatigue (FSS) Inconclusive NR NR NR NR Only (1996)18 reported that the between group difference was not significant Mokhtarza Aerobic exercise No treatment 0.72 Fatigue (FSS) Favors 3.45 2.67 3.51 3.56 de (0.09 to 1.35) exercise (SD: 0.87) (SD:1.28) (SD: 1.11) (SD:1.16) (2017)40 (N=22) (N=18) Hasanpou Exercise walking No treatment 1.56 Fatigue (Rhoten Favors 4.9 2.55 3.8 3.55 r (2016)59 (0.86 to 2.26) Fatigue Scale) exercise (SD: 1.333) (SD:0.944) (SD: 1.641) (SD:1.234) (N=20) (N=21) Mokhtarza Aerobic exercise No treatment 0.82 QOL Favors 54.21 63.78 52.2 50.87 de (0.18 to 1.46) (MSQOL-54) aerobic (SD: 14.63) (SD:12.47) (SD: 12.91) (SD:11.2) (2017)40 exercise (N=22) (N=18) Hasanpou Exercise walking No treatment 1.42 QOL (SF-36 Favors 44.14 52.12 42.2 38.12 r (2016)59 (0.73 to 2.11) physical exercise (SD: 7.38) (SD:9.87) (SD: 8.3) (SD:7.88) functioning) (N=20) (N=21) Petajan Exercise No treatment 1.12 QOL (SIP total Favors 94.4 68.5 65.9 65.7 (1996)18 (0.49 to 1.74) [higher score is exercise (SD: 29.6) (SD:24.7) (SD: 19) (SD:18.1) worse]) (N=21) (N=25)

79 Table 7. Fatigue And Quality of Life Data for Evidence Map 2: Exercise Interventions, continued

Trial Group 1 Group 2 Hedges' g Outcome Single Study Group 1 Group 1 Group 2 Group 2 Comments Specific Specific (95% CI) (Instrument) Finding Baseline Outcome Baseline Outcome Treatment Inactive Mean (SD) Mean (SD) Mean (SD) Mean (SD) Treatment (N at (N at Follow-up) Follow-up) Dalgas Progressive Usual care 0.4 Fatigue (FSS) Inconclusive 5.8 4.9 5.5 5.1 (2010)33 resistance (-0.29 to 1.1) (SD: 0.65) (SD:1.12) (SD: 0.9) (SD:1.63) training (N=16) (N=15) Dodd Exercise Usual care -0.06 Fatigue (MFIS) Inconclusive 41.9 39 40 36.2 (2011)51 resistance plus attention (-0.54 to 0.42) (SD: 14) (SD:14.7) (SD: 15.8) (SD:16.2) training and social (N=36) (N=31) program Dalgas Progressive Usual care 0.69 QOL (SF-36 Inconclusive 41.4 45.3 42.6 41.5 (2010)33 resistance (-0.01 to 1.4) physical (SD: 7.32) (SD:7.23) (SD: 7.32) (SD:5.96) training functioning) (N=16) (N=15) Dodd Exercise Usual care -0.2 QOL (WHOQOL- Inconclusive 3.8 3.7 3.9 4 (2011)51 resistance plus attention (-0.68 to 0.28) BREF) (SD: 0.9) (SD:1.1) (SD: 1) (SD:1) training and social (N=36) (N=31) program Razazian Yoga Usual care 1.81 Fatigue (FSS) Favors yoga 38.94 16.22 39.56 41.22 (2016)61 (1.05 to 2.57) (SD: 13.63) (SD:9.6) (SD: 14.68) (SD:13.52) (N=18) (N=18) Garrett Yoga No treatment 0.42 Fatigue (MFIS Favors yoga NR NR NR NR Used (2013)62 (0.04 to 0.79) total) reported CIs of individual group change scores to calculate Hedges' g Oken Yoga Waitlist 0.44 Fatigue Inconclusive 14.7 13 15.2 14.9 (2004)60 (-0.17 to 1.05) (Multidimensiona (SD: 3.3) (SD:2.9) (SD: 3.4) (SD:3) l Fatigue (N=22) (N=20) Inventory [MFI]) Hasanpou Yoga No treatment 0.78 Fatigue (Rhoten Favors yoga 4.75 3.35 3.8 3.55 r (2016)59 (0.14 to 1.41) Fatigue Scale) (SD: 1.712) (SD:0.812) (SD: 1.641) (SD:1.234) (N=20) (N=21)

80 Table 7. Fatigue And Quality of Life Data for Evidence Map 2: Exercise Interventions, continued

Trial Group 1 Group 2 Hedges' g Outcome Single Study Group 1 Group 1 Group 2 Group 2 Comments Specific Specific (95% CI) (Instrument) Finding Baseline Outcome Baseline Outcome Treatment Inactive Mean (SD) Mean (SD) Mean (SD) Mean (SD) Treatment (N at (N at Follow-up) Follow-up) Garrett Yoga No treatment 0.28 QOL (MSIS-29 Inconclusive Used (2013)62 (-0.09 to 0.65) Physical [higher (SD: NR) (SD:NR) (SD: NR) (SD:NR) reported scores are (N=63) (N=49) CIs of WORSE]) individual group change scores to calculate Hedges' g Hasanpou Yoga No treatment 1.58 QOL (SF-36 Favors yoga 40.1 50.14 42.2 38.12 r (2016)59 (0.87 to 2.28) physical (SD: 7.16) (SD:11.15) (SD: 8.3) (SD:7.88) functioning) (N=20) (N=21) Oken Yoga Waitlist 0.09 QOL (SF-36 Inconclusive 58.6 61 58.1 58.1 (2004)60 (-0.52 to 0.69) physical (SD: 31.6) (SD:31.6) (SD: 19) (SD:23.3) functioning) (N=22) (N=20) Rietberg Multidisciplinary Nurse 0.17 Fatigue (CIS- Inconclusive 78 81 79 80 (2014)26 rehabilitation consultation (-0.43 to 0.76) 20R) (SD: 13.5) (SD:9.5) (SD: 13) (SD:11) (N=21) (N=23) Nedeljkovi Rehabilitation + High-dose 0.35 Fatigue (FSS) Inconclusive 43.1 36.6 41.1 40.6 c (2016)31 high-dose methylpred- (-0.27 to 0.97) (SD: 15.3) (SD:21.1) (SD: 12.9) (SD:15.9) methylprednisolone (N=19) (N=20) nisolone Rietberg Multidisciplinary Nurse 0.4 Fatigue (MFIS) Inconclusive 43 42 36 42 (2014)26 rehabilitation consultation (-0.2 to 1) (SD: 18.75) (SD:11) (SD: 14.5) (SD:21) (N=21) (N=23) Rietberg Multidisciplinary Nurse 0.3 QOL (MSIS-29 Inconclusive 53 45 43 41 (2014)26 rehabilitation consultation (-0.29 to 0.9) Physical [higher (SD: 20) (SD:19.5) (SD: 19) (SD:21) scores are (N=21) (N=23) WORSE]) Carter Supervised Usual care 0.23 Fatigue (MFIS) Inconclusive 45 39.6 42.8 41.3 (2014)44 exercise and (-0.17 to 0.62) (SD: 17) (SD:16.6) (SD: 15.7) (SD:18.8) CBT (N=49) (N=50) Carter Supervised Usual care 0.46 QOL (MSQoL-54 Favors 58.3 65.9 62.4 60.4 (2014)44 exercise and (0.06 to 0.86) Overall) supervised (SD: 21.8) (SD:20.1) (SD: 20.3) (SD:21.1) CBT exercise with (N=49) (N=50) CBT

81 Table 7. Fatigue And Quality of Life Data for Evidence Map 2: Exercise Interventions, continued

Table 8. Fatigue and Quality of Life Data for Evidence Map 2: Behavioral/Educational Interventions Trial Group 1 Group 2 Hedges' g Outcome Single Study Group 1 Group 1 Group 2 Group 2 Comments Specific Specific (95% CI) (Instrument) Finding Baseline Outcome Baseline Outcome Treatment Inactive Mean (SD) Mean (SD) Mean (SD) Mean (SD) Treatment (N at (N at Follow-up) Follow-up) Pilutti Behavioral Waitlist 0.64 Fatigue (FSS) Favors 4.6 5.4 (2014)48 intervention (0.18 to 1.1) behavioral (SD: NR) (SD:1.22) (SD: NR) (SD:1.25) to encourage intervention (N=37) (N=39) physical activity via education Motl Education Waitlist 0.5 Fatigue (FSS) Inconclusive 5.1 4.4 4.9 4.9 (2017)56 with website (-0.09 to 1.1) (SD: 1) (SD:0.96) (SD: 1.2) (SD:0.89) and video (N=23) (N=20) chats Turner Telephone Self-directed 0.71 Fatigue (MFIS) Favors 53.78 44.73 49.65 49.7 (2016)28 counseling education (0.2 to 1.22) telephone (SD: 14.6) (SD:15.2) (SD: 14.6) (SD:15.22) counseling (N=30) (N=33) Motl Education Waitlist 0.75 Fatigue (MFIS) Favors 44.5 36.8 42.7 44.7 (2017)56 with website (0.13 to education (SD: 14.2) (SD:10.55) (SD: 17.5) (SD:10.29) and video 1.37) (N=23) (N=20) chats Pilutti Behavioral Waitlist 0.43 Fatigue (MFIS Inconclusive 35.7 40.5 (2014)48 intervention (-0.02 to total) (SD: NR) (SD:10.9) (SD: NR) (SD:11.2) to encourage 0.89) (N=37) (N=39) physical activity via education Pilutti Behavioral Waitlist 0.44 QOL (MSIS-29 Inconclusive 29.1 33.2 (2014)48 intervention (-0.01 to 0.9) Physical (higher (SD: NR) (SD:9.1) (SD: NR) (SD:9.4) to encourage scores are (N=37) (N=39) physical WORSE)) activity via education Afrasiabifar Oren's self- No treatment 2.43 Fatigue (FSS) Favors Oren's 6.22 1.68 6.04 6.45 (2016)43 care model (1.77 to model (SD: 2.06) (SD:2.171) (SD: 2.227) (SD:1.448) (education) 3.08) (N=31) (N=31) Shinto Education Usual care -0.13 Fatigue (MFIS) Inconclusive (2008)52 (-0.83 to (SD: NR) (SD:NR) (N=) (SD: NR) (SD:NR) 0.57) (N=)

Table 8. Fatigue and Quality of Life Data for Evidence Map 2: Behavioral/Educational Interventions

Trial Group 1 Group 2 Hedges' g Outcome Single Study Group 1 Group 1 Group 2 Group 2 Comments Specific Specific (95% CI) (Instrument) Finding Baseline Outcome Baseline Outcome Treatment Inactive Mean (SD) Mean (SD) Mean (SD) Mean (SD) Treatment (N at (N at Follow-up) Follow-up) Shinto Education - Usual care 0.3 QOL (SF-36 Inconclusive (2008)52 series of 8 (-0.4 to 1.01) physical (SD: NR) (SD:NR) (SD: NR) (SD:NR) visits with MS functioning) (N=NR) (N=NR) nurse to go over information in a MS pamphlet Blikman Energy Education with 0.22 Fatigue (CIS- Inconclusive 44.3 40.9 43.6 42.1 (2017)37 conservation nurse (-0.25 to 0.7) 20R Fatigue) (SD: 7.9) (SD:9.6) (SD: 7.1) (SD:8.9) management consultations (N=34) (N=35) Thomas FACETS Usual care 0.43 Fatigue (Global Favors 5.6 5.26 5.61 5.66 (2013)49 program (0.1 to 0.76) Fatigue Severity FACETS (SD: 0.98) (SD:1.03) (SD: 1.09) (SD:0.93) (CBT, social [GFS]) (N=70) (N=74) cognitive, energy effectiveness, self- management) Thomas FACETS Usual care 0.11 QOL (MSIS Inconclusive 49.6 44.9 43.9 43 (2013)49 program (-0.22 to [higher scores (SD: 19.1) (SD:19.2) (SD: 17.6) (SD:17.3) (CBT, social 0.43) are worse]) (N=70) (N=74) cognitive, energy effectiveness, self- management) Ghahari Online Usual care 0.21 Fatigue (Fatigue Inconclusive 79.94 64.29 76.36 67.64 (2010)30 education (-0.27 to Impact Scale (SD: 30.48) (SD:34.25) (SD: 32.16) (SD:36.69) with 0.69) [FIS]) (N=34) (N=33) interactive components Finlayson Fatigue Waitlist 0.61 Fatigue (Fatigue Favors (2011)34 management (0.5 to 0.72) Impact Scale fatigue (SD: NR) (SD:NR) (SD: NR) (SD:NR) program via [FIS] Physical management (N=68) (N=70) tele- [FIS total was via teleconference not reported]) conference

84 Table 8. Fatigue and Quality of Life Data for Evidence Map 2: Behavioral/Educational Interventions

Trial Group 1 Group 2 Hedges' g Outcome Single Study Group 1 Group 1 Group 2 Group 2 Comments Specific Specific (95% CI) (Instrument) Finding Baseline Outcome Baseline Outcome Treatment Inactive Mean (SD) Mean (SD) Mean (SD) Mean (SD) Treatment (N at (N at Follow-up) Follow-up) Finlayson Fatigue Waitlist 0.33 Fatigue (FSS) Favors (2011)34 management (0.3 to 0.36) fatigue (SD: NR) (SD:NR) (SD: NR) (SD:NR) program via management (N=68) (N=70) tele- via teleconference conference Hugos Fatigue Usual care -0.07 Fatigue (FSS) Inconclusive 52.47 49.13 51.53 47.4 (2010)35 management (-0.76 to (SD: 11.3) (SD:11.3) (SD: 11.3) (SD:11.3) program 0.63) (N=15) (N=15) (6 weeks) Kos fatigue Education (not NR Fatigue (MFIS) Inconclusive NR NR NR NR Only (2007)23 management related to reported program fatigue) different (4 weeks) between groups in proportion of patients with >=10 point change in MFIS (no CI's reported, just effect size) Hugos Fatigue Usual care 0.2 Fatigue (MFIS) Inconclusive 44 39.79 45.87 44.4 (2010)35 management (-0.5 to 0.9) (SD: 13.4) (SD:13.4) (SD: 12.97) (SD:12.97) program (N=15) (N=15) (6 weeks) Blikman Energy Education with 0.11 Fatigue (MFIS Inconclusive 45.1 41.4 42.7 40.6 (2017)37 conservation nurse (-0.36 to total) (SD: 11.7) (SD:13.9) (SD: 14.4) (SD:16.7) management consultations 0.58) (N=34) (N=35) Ghahari Online Usual care 0.05 QOL (Personal Inconclusive 57.18 60.92 58.74 61.36 (2010)30 education (-0.42 to Well Being (SD: 21.56) (SD:20.91) (SD: 19.3) (SD:20.07) with 0.53) Scale) (N=34) (N=33) interactive components Finlayson Fatigue Waitlist 0.27 QOL (SF-36 Favors NR NR NR NR Cohen’s D (2011)34 management (0.17 to physical function fatigue from the program via 0.37) (SF-36 total was management authors’ tele- not reported)) via tele- Table 5 conference conference 85 Table 8. Fatigue and Quality of Life Data for Evidence Map 2: Behavioral/Educational Interventions

Trial Group 1 Group 2 Hedges' g Outcome Single Study Group 1 Group 1 Group 2 Group 2 Comments Specific Specific (95% CI) (Instrument) Finding Baseline Outcome Baseline Outcome Treatment Inactive Mean (SD) Mean (SD) Mean (SD) Mean (SD) Treatment (N at (N at Follow-up) Follow-up) Blikman Individual Education with 0.25 QOL (SF-36 Inconclusive 53.9 55.4 59.2 54 (2017)37 energy nurse (-0.22 to physical function (SD: 24.8) (SD:25.7) (SD: 26.4) (SD:28.5) conservation consultations 0.73) (SF-36 total was (N=34) (N=35) management not reported)) with occupational therapist Moss- CBT (internet No treatment 1.27 Fatigue (Chalder Favors CBT 21.39 12.39 21.53 19.57 Morris based) (0.56 to Fatigue scale) (SD: 4.3) (SD:6.84) (SD: 3.62) (SD:5.2) (2012)36 1.97) (N=20) (N=16) van den CBT Nurse -0.08 Fatigue (CIS- Inconclusive 42.9 38.9 44.2 39.5 Akker consultations (-0.54 to 20R Fatigue) (SD: 8.5) (SD:9.7) (SD: 6) (SD:9) (2017)38 0.38) (N=39) (N=35) van den CBT Nurse 0 Fatigue (FSS) Inconclusive 5.4 5 5.5 5.1 Akker consultations (-0.45 to (SD: 0.7) (SD:0.9) (SD: 0.8) (SD:0.9) (2017)38 0.45) (N=39) (N=37) Moss- CBT (internet No treatment 1.11 Fatigue (MFIS) Favors CBT 13.17 9 12.69 12.88 Morris based) (0.43 to 1.8) (SD: 3.81) (SD:3.75) (SD: 3.89) (SD:3.89) (2012)36 (N=21) (N=16) van den CBT Nurse -0.31 Fatigue (MFIS Inconclusive 47.3 42.5 47.7 39.1 Akker consultations (-0.76 to total) (SD: 12.5) (SD:12.2) (SD: 9.6) (SD:13.8) (2017)38 0.14) (N=39) (N=37) Kiropoulos CBT Usual care 0.97 Fatigue (MFIS-5) Favors CBT 12.13 8.06 12.26 11.93 (2016)46 (0.23 to (SD: 3.58) (SD:3.03) (SD: 3.84) (SD:4.38) 1.71) (N=15) (N=15) Kiropoulos CBT Usual care 0.51 QOL (MSQOL- Inconclusive 47.39 63.32 43.28 49.33 (2016)46 (-0.2 to 1.22) 54) (SD: 18.07) (SD:17.25) (SD: 17.63) (SD:21.32) (N=15) (N=15) van den CBT Nurse 0.09 QOL (SF-36 Inconclusive 55.8 55.9 62.2 60.3 Akker consultations (-0.36 to physical function (SD: 22.1) (SD:22.3) (SD: 20.4) (SD:22) (2017)38 0.54) (SF-36 total was (N=39) (N=37) not reported)) Rosti- Outpatient No treatment 0.19 Fatigue (FSMC Inconclusive 64.2 59 66.3 64.4 Otajarvi neuropsycho- (-0.27 to total score) (SD: 18.7) (SD:17.7) (SD: 15.6) (SD:16.5) (2013)54 logical 0.65) (N=50) (N=28) rehabilitation

86 Table 8. Fatigue and Quality of Life Data for Evidence Map 2: Behavioral/Educational Interventions

Trial Group 1 Group 2 Hedges' g Outcome Single Study Group 1 Group 1 Group 2 Group 2 Comments Specific Specific (95% CI) (Instrument) Finding Baseline Outcome Baseline Outcome Treatment Inactive Mean (SD) Mean (SD) Mean (SD) Mean (SD) Treatment (N at (N at Follow-up) Follow-up) Pérez- Cognitive Received a 0.21 Fatigue (FSS) Inconclusive 34.73 30.51 28.89 29.21 Martín rehabilitation book containing (-0.29 to (SD: 21.97) (SD:20.22) (SD: 21.79) (SD:21.94) (2017)41 training guidelines and 0.71) (N=30) (N=32) general advice, and were contacted once a week De Giglio Cognitive Usual care 0.54 Fatigue (MFIS) Inconclusive 36.47 28.5 32.69 32.69 (2015)53 training (-0.13 to (SD: 13.8) (SD:14.56) (SD: 14.095) (SD:14.91) (video 1.21) (N=18) (N=16) console) Rosti- Outpatient No treatment 0.01 QOL (MSIS-29 Inconclusive 25 22.9 26.1 24.2 Otajarvi neuropsycho- (-0.45 to Physical [higher (SD: 16.9) (SD:15.5) (SD: 17.2) (SD:14) (2013)54 logical 0.47) scores are (N=50) (N=28) rehabilitation WORSE]) Pérez- Cognitive Received a 0.88 QOL (MSQoL-54 Favors 46.43 52.99 63.75 63.24 Martín rehabilitation book containing (0.36 to 1.4) Physical) cognitive (SD: 17.83) (SD:19.2) (SD: 17.27) (SD:16.98) (2017)41 training guidelines and rehabilitation (N=30) (N=32) general advice, training and were contacted once a week De Giglio Cognitive Usual care -0.23 QOL (MSQOL- Inconclusive 60.09 62.7 57.04 62.72 (2015)53 training (-0.89 to 54 Physical (SD: 11.33) (SD:11.84) (SD: 14.67) (SD:14.84) (video 0.43) Health (N=18) (N=16) console) Composite) Bogosian Mindfulness Usual care -0.24 Fatigue (FSS) Inconclusive 39.91 43.87 48.29 49.08 (2015)47 (online) (-0.91 to (SD: 14.45) (SD:13.39) (SD: 12.24) (SD:12.43) 0.43) (N=15) (N=18) Grossman Mindfulness Usual care 0.57 Fatigue (MFIS) Favors 35.15 30.28 Used (2010)24 based (0.23 to mindfulness (SD: 16.68) (SD:NR) (SD: 14.98) (SD:NR) reported intervention 0.91) (N=72) (N=67) CIs of individual group change scores to calculate Hedges' g Bogosian Mindfulness Usual care 0.23 QOL (Euro QOL Inconclusive 0.41 0.51 0.48 0.5 (2015)47 (online) (-0.46 to [EQ-5D]) (SD: 0.39) (SD:0.37) (SD: 0.33) (SD:0.29) 0.91) (N=14) (N=18) 87 Table 8. Fatigue and Quality of Life Data for Evidence Map 2: Behavioral/Educational Interventions

Table 9. Fatigue And Quality of Life Data for Evidence Map 2: Complementary and Alternative Medicine (CAM) Interventions Trial Group 1 Group 2 Hedges' g Outcome Single Study Group 1 Group 1 Group 2 Group 2 Comments Specific Specific (95% CI) (Instrument) Finding Baseline Outcome Baseline Outcome Treatment Inactive mean (SD) Mean (SD) Mean (SD) Mean (SD) Treatment (N at (N at Follow-up) Follow- up) Wade Lofepramine Placebo 0.36 Fatigue (Chalder Favors Lofepramine 3.9 1.8 3.4 2.5 (2002)20 and L- (0.02 to 0.7) Fatigue scale) and L-phenylalanine (SD: 3.4) (SD:3.2) (SD: 3.5) (SD:3.2) phenylalanine (N=67) (N=67) Torkildsen Omega-3 fatty Placebo NR Fatigue (FSS) Inconclusive NR NR NR NR Only (2012)50 acids reported that p=0.97 Torkildsen Omega-3 fatty Placebo NR QOL (SF-36 Inconclusive NR NR NR NR Only (2012)50 acids Physical) reported that p=0.53 FSS- Fatigue Severity Scale MFIS – Modified Fatidue Impact Scale NR – Not reported QOL – Quality of life SD – Standard deviation

Table 10. Fatigue And Quality of Life Data for Evidence Map 2: Other Interventions Trial Group 1 Group 2 Hedges' g Outcome Single Study Group 1 Group 1 Group 2 Group 2 Specific Specific (95% CI) (Instrument) Finding Baseline Mean Outcome Mean Baseline Mean Outcome Mean Treatment Inactive (SD) (SD) (SD) (SD ) Treatment (N at Follow-up) (N at Follow-up) de Carvalho Low frequency Sham 0.14 Fatigue (FSS) Inconclusive 49.9 46.5 53.3 48 (2012)29 magnetic stimulation (-0.41 to 0.7) (SD: 12.5) (SD:16) (N=25) (SD: 9.1) (SD:14) (N=25) stimulation de Carvalho Low frequency Sham -0.37 Fatigue (MFIS) Inconclusive 41.6 46 47.2 45 (2012)29 magnetic stimulation (-0.92 to (SD: 13.6) (SD:23) (N=25) (SD: 15.6) (SD:16) (N=25) stimulation 0.19) Piatkowski electromagnetic Sham 0.27 Fatigue (MFIS) Inconclusive 31.68 26.84 37.83 36.67 (2009)32 field therapy therapy (-0.36 to (SD: 13.24) (SD:12.06) (SD: 14.26) (SD:13.25) 0.91) (N=19) (N=18) FSS- Fatigue Severity Scale MFIS – Modified Fatidue Impact Scale NR – Not reported QOL – Quality of life SD – Standard deviation

Table 11. Adverse Effects Data for Evidence Map 2 Group 2 Group 1 Specific Judgment of AE Specific Inactive Rate in Rate in Severity for This Trial Treatment Treatment Adverse Effect Group 1 Group 2 Study Comments Rossini (2001) 4-AP Placebo Transient side effects 33% (9/27) 9% (2/22) Moderate Krupp (1995) Amantadine Placebo Side effects not severe 16% (5/31) 9% (3/35) Mild Amantadine: 2 sleep enough to cause study disturbances, 1 palpitations, withdrawal 2 unspecified. Placebo: 1 headache and 2 unspecified. Side effects severe enough 6% (2/31) 3% (1/35) Mild Causes of withdrawal from to cause study withdrawal amantadine were rash and anxiety. Cause of withdrawal from placebo was excessive sleep disturbance Sadeghi-Naini Aspirin Placebo Any serious AE 0% (0/51) 0% (0/49) Mild (2017) Study withdrawal after the 4% (2/51) 8% (4/49) Mild first visit due to severe depression Study withdrawal mid 4% (2/51) 4% (2/49) Mild treatment due to GI complaints Study withdrawal mid 2% (1/51) 6% (3/49) Mild treatment due to other reasons Moller (2011) Modafinil Placebo Any serious AE 0% (0/55) 0% (0/55) Moderate Increased uneasiness/ NR NR Moderate Trend of increased rate in restlessness modafinil group p=0.07, rates not reported Nausea NR NR Moderate Trend of increased nausea in modafinil group p=0.08, rates not reported Other side effects (NR) NR NR Moderate More “other side effects” in modafinil group p=0.01 Ehde (2008) Paroxetine No treatment Dry mouth 47% (8/17) 32% (6/19) Mild Headache 47% (8/17) 11% (2/19) Mild Nausea 65% (11/17) 5% (1/19) Severe Sexual dysfunction 24% (4/17) 5% (1/19) Mild Tarakci (2013) Group exercise Monthly phone Any 0% (0/51) 0% (0/48) Mild led by physical call from a therapist neurologist

Table 11. Adverse Effects Data for Evidence Map 2, continued

Group 2 Group 1 Specific Judgment of AE Specific Inactive Rate in Rate in Severity for This Trial Treatment Treatment Adverse Effect Group 1 Group 2 Study Comments van den Akker CBT Nurse Serious AE during followup 9% (3/34) 3% (1/35) Mild Two MS relapses in the CBT (2017) consultations group and one surgery. Control group had one MS relapse. Judged to be unrelated to interventions. Serious AE during treatment 3% (1/34) 6% (2/35) Mild One MS relapse in the CBT period group. Control group had one MS relapse and one gall bladder surgery. Judged to be unrelated to interventions. Shinto (2008) Education Usual care Any serious AE 0% (0/15) 0% (0/15) Mild MS relapse 13% (2/15) 7% (1/15) Mild Thomas (2013) FACETS Usual care Any 0% (0/70) 0% (0/74) Mild program (CBT, Any 0% (0/70) 0% (0/74) Mild social cognitive, energy effectiveness, self- management) Dodd (2011) Psychological No treatment Injury requiring participant to 0% (0/37) 0% (0/31) Mild training with miss a training session gradual muscle Muscle stiffness NR NR Mild Table 4 of the author’s report relaxation (bottom) shows inconclusive data on the MSSS-88 instrument, on whether there was a group difference in muscle stiffness (wide CIs at both time intervals) Motl (2017) Education with Waitlist Any adverse events 0% (0/23) 0% (0/20) Mild website and video chats Turner (2016) Telephone Self-directed Worsening of MS symptoms NR NR Mild On average participants counseling education as measured by the MS- reported fewer MS symptoms symptom related checklist over time, in both groups. No difference between groups, suggesting no AEs of telephone counseling

92 Table 11. Adverse Effects Data for Evidence Map 2, continued

Group 2 Group 1 Specific Judgment of AE Specific Inactive Rate in Rate in Severity for This Trial Treatment Treatment Adverse Effect Group 1 Group 2 Study Comments Wade (2002) Lofepramine and Placebo Back pain 3% (2/69) 9% (6/69) Moderate L-phenylalanine Constipation 46% (32/69) 14% (10/69) Moderate Depression 17% (12/69) 13% (9/69) Moderate Diarrhea 3% (2/69) 10% (7/69) Moderate Dry mouth 32% (22/69) 10% (7/69) Moderate Fatigue 12% (8/69) 17% (12/69) Moderate Headache 14% (10/69) 19% (13/69) Moderate Hot flushes 12% (8/69) 1% (1/69) Moderate Insomnia 19% (13/69) 6% (4/69) Moderate Nausea 19% (13/69) 9% (6/69) Moderate Palpitations 13% (9/69) 3% (2/69) Moderate UTI 13% (9/69) 20% (14/69) Moderate Torkildsen Omega-3 fatty Placebo Abdominal pain 0% (0/46) 7% (3/46) Mild (2012) acids Any 74% (34/46) 63% (29/46) Mild Arthralgia 7% (3/46) 7% (3/46) Mild Cod liver oil gulp 9% (4/46) 2% (1/46) Mild Fatigue 11% (5/46) 9% (4/46) Mild Hair loss 7% (3/46) 0% (0/46) Mild Headache 9% (4/46) 9% (4/46) Mild Low back pain 4% (2/46) 7% (3/46) Mild Myalgia 4% (2/46) 22% (10/46) Mild Nausea 7% (3/46) 9% (4/46) Mild Serious AE 9% (4/46) 2% (1/46) Mild Stated to be unrelated to study drug UTI 9% (4/46) 7% (3/46) Mild Withdrawal due to AEs 2% (1/46) 4% (2/46) Mild 1 omega-3 withdrawal due to nausea. Two placebo withdrawals due to allergic reactions. de Carvalho Low frequency Sham stimulation Any 0% (0/25) 0% (0/25) Mild “No side effects were (2012) magnetic recorded” stimulation AE – Adverse effect MS – Multiple sclerosis NR – Not reported SD – Standard deviation UTI – Urinary tract infection 93

Table 12. Fatigue Data for Evidence Map 3 Hedges' g (95% CI) Group 1 Group 2 (Positive Outcome Outcome Group 1 Group 2 Number Group 1 Mean (SD) Group 2 Mean (SD) Specific Specific Outcome Favors Single Study Baseline (N at Baseline (N at Trial Treatment Treatment (Instrument) Group 1) Finding Mean (SD) follow-up) Mean (SD) Follow-up) Comments van Kessel CBT Relaxation Fatigue (Fatigue 0.52 Favors CBT 20.94 10.37 20.32 12.49 (2008)64 training Scale) (0.04 to 1) (SD: 4.25) (SD:6.37) (SD: 4.28) (SD:5.24) (N=34) (N=35) Mohr Individual CBT Group Fatigue (Fatigue 0.68 Favors 150.1 140.4 151.3 153.8 (2003)65 psychotherapy Assessment (0.07 to 1.29) individual CBT (SD: 14.21) (SD:22.39) (SD: 15.7) (SD:16.58) Instrument (FAI) (N=22) (N=22) total) Mohr Group Sertraline Fatigue (Fatigue -0.74 Favors 151.3 153.8 152.1 139 (2003)65 psychotherapy Assessment (-1.4 to -0.07) sertraline (SD: 15.7) (SD:16.58) (SD: 22.62) (SD:29.35) Instrument (FAI) (N=22) (N=16) total) Gandolfi Sensory Conventional Fatigue (FSS) 0.59 Favors 4.1 3.15 4.37 4.4 (2015)67 integration rehabilitation (0.11 to 1.07) sensory (SD: 1.82) (SD:1.6) (SD: 1.59) (SD:1.59) balance training integration (N=32) (N=36) balance training Oken Exercise Yoga Fatigue (Multi- -0.18 Inconclusive 13.2 12.1 14.7 13 (2004)60 stationery bike dimensional (-0.84 to 0.48) (SD: 4) (SD:2.8) (SD: 3.3) (SD:2.9) Fatigue (N=15) (N=22) Inventory [MFI]) Hasanpour Exercise walking Yoga Fatigue (Rhoten 0.71 Favors 4.9 2.55 4.75 3.35 (2016)59 Fatigue Scale) (0.07 to 1.35) exercise (SD: 1.333) (SD:0.944) (SD: 1.712) (SD:0.812) (N=20) (N=20) Romani 4'aminopyridine Fluoxetine Fatigue (FSS) 0.21 Inconclusive 6.8 5.5 6.9 5.7 (2004)63 (-0.44 to 0.86) (SD: NR) (SD:NR) (SD: NR) (SD:NR) (N=18) (N=17) Tomassini Amantidine L-carnitine Fatigue (FSS) -0.01 Inconclusive NR NR NR NR Only absolute (2004)66 (-0.72 to 0.69) change at 3 months reported with CIs: L-carnitine: -0.2 (-4.75 to 0.05); amantadine: -0.15 (-0.075 to 0.375): SD carnitine 4.68; SD amantadine 0.37

Table 12. Fatigue Data for Evidence Map 3 Hedges' g (95% CI) Group 1 Group 2 (Positive Outcome Outcome Group 1 Group 2 Number Group 1 Mean (SD) Group 2 Mean (SD) Specific Specific Outcome Favors Single Study Baseline (N at Baseline (N at Trial Treatment Treatment (Instrument) Group 1) Finding Mean (SD) follow-up) Mean (SD) Follow-up) Comments Straudi Robot-assisted Conventional Fatigue (FSS) NR Inconclusive NR NR NR NR Only reported (2016)68 gait training walking that the between therapy group difference was NS Kalron Pilates PT Fatigue (MFIS) -0.05 Inconclusive 35.3 34.7 30.4 28.7 (2017)69 (-0.64 to 0.53) (SD: 21.6) (SD:19.5) (SD: 22.3) (SD:21.7) (N=22) (N=23) Kerling Combined Endurance Fatigue (MFIS) 0.01 Inconclusive 35.5 30.6 35.1 30.3 (2015)71 endurance and exercise (-0.63 to 0.64) (SD: 17) (SD:16.7) (SD: 17.4) (SD:18.1) resistance (N=19) (N=18) exercise Garrett Exercise led by Yoga Fatigue (MFIS) 0.1 Inconclusive NR NR NR NR We used the (2013)62 physiotherapist (-0.2 to 0.4) (SD: NR) (SD:NR) (SD: NR) (SD:NR) reported CIs of or fitness (N=63) (N=63) individual group instructor change scores to calculate Hedges' g Aydin Supervised Exercise Fatigue (FSS) -0.1 Inconclusive 4.79 4.86 4.44 4.37 (2014)72 exercise (calisthenic + (-0.75 to 0.54) (SD: 1.18) (SD:1.16) (SD: 1.43) (SD:1.43) (calisthenic + relaxation), (N=16) (N=20) relaxation) home Razazian Yoga Aquatic Fatigue (FSS) -0.06 Inconclusive 38.94 16.22 48.72 25.28 (2016)61 exercise (-0.7 to 0.58) (SD: 13.63) (SD:9.6) (SD: 11.46) (SD:11.71) (N=18) (N=18) Mohr Individual CBT Sertraline Fatigue (Fatigue -0.15 Inconclusive 150.1 140.4 152.1 139 (2003)65 Assessment (-0.79 to 0.5) (SD: 14.21) (SD:22.39) (SD: 22.62) (SD:29.35) Instrument (FAI) (N=22) (N=16) total) Ehde Telephone Education with Fatigue (MFIS) -0.01 Inconclusive 48 40.2 51.2 43.3 (2015)70 delivered self- follow-up calls (-0.34 to 0.33) (SD: 14.7) (SD:16.5) (SD: 12.7) (SD:15.8) management (N=60) (N=80) Eyssen Client-centered Standard Fatigue (MFIS) 0.01 Inconclusive 45.75 48.75 (2013)73 occupational occupational (-0.26 to 0.29) (SD: 14.01) (SD:NR) (SD: 13.61) (SD:NR) therapy therapy (N=107) (N=100) FSS- Fatigue Severity Scale MFIS – Modified Fatidue Impact Scale NR – Not reported QOL – Quality of life SD – Standard deviation

Appendix E. September 2018 Map Updates This appendix lists all map updates made in August‐September 2018.

Map 1 Updates

 For RCTs, Map 1 uses small interior bubbles to show specific interventions within each of the six categories. These appear when the user clicks the checkbox “Specific interventions.”  The interior bubbles are sized proportionally to the number of patients enrolled in RCTs for each specific treatment.  Hovering over an interior bubble shows the name of the specific treatment, and the number of patients enrolled in RCTs of that specific treatment.  The updated footnote describes what the smaller bubbles mean.  We edited “controlled study” to “controlled non‐randomized trial” (for clarity).  Colors have been adjusted for easier visibility.  The Map footnote was edited to describe the addition of the interior bubbles for specific interventions.

Map 2 Updates

 Records identified in clinicaltrials.gov appear as blacked dashed outlines when the user checks the box on the left labelled “show clinicaltrials.gov records.”  We added a legend (black dashed circle) to indicate records in clinicaltrials.gov.  Some interventions have been added to the Map, because they were only found in records in clinicaltrials.gov.  Hovering over any bubble with a black dashed circle will display a link to the pertinent record in clinicaltrials.gov.  Thickness of PCORI blue outlines was increased, for better visibility.  For PCORI‐funded trials, we changed the wording from “additional PCORI trial ongoing” to “Ongoing PCORI‐funded studies.”  Arrows for minimizing/maximizing treatment categories have been enlarged and made into blue boxes, to enhance user understanding of their purpose.  For green bubbles, we translated Hedges’ g effect size into either the 1–7 FSS scale or the 0–84 MFIS scale for better interpretability.  If a hover or footnote mentions the FSS or the MFIS, a link is provided to the specific items on those scales.  The names of specific QOL scales names now appear in the hovers for QOL bubbles.  For adverse effects, the hover now indicates mild/moderate/severe rather than 0.2/0.5/0.8.  For adverse effects, when a user clicks for more information about specific AE’s, the resulting web page highlights in yellow the pertinent study in the AE table to improve usability.  The Map footnote was edited to reflect the addition of the clinicaltrials.gov filter.  We added direct hyperlink to MFIS and FSS scales in the map footnote.

Table 12. Fatigue Data for Evidence Map 3

Map 3 Updates

 We added a legend (black dashed circle) to indicate records in clinicaltrials.gov.  When one active intervention was favored over another, the bubble is now green. In the previous version, it was dark red, possibly causing confusion with the red AE bubbles in Map 2.  Headers for columns and rows were changed to dark gray to improve visibility.  We added hyperlinks to the eight additional clinicaltrials.gov records making novel comparisons (i.e., not in the existing evidence base) in the footnote.