pcori map · fatigue and quality of life data for evidence map 2: exercise interventions ..... 78...

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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

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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

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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

1

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,

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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).

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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.

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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

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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:

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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

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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%.

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Figure 1. Article Flow

1,718 publications identified

Abstracts screened

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

Full text reviewof 178 randomized

trials

122 randomized trials excluded:50: <8 weeks follow-up34: Follow-up Ns <15 per group30: Just an abstract4: Only compared active treatments, and only one was of interest2: Did not report results for fatigue, quality of life or adverse effects1: Did not report comparative post-treatment data1: Did not report comparative data past 8 weeks

EVIDENCE MAP 2:45 randomized trialsActive vs. inactive

1,436 excluded from all maps

EVIDENCE MAP 3: 15 randomized trials

Active vs. active

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

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

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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.

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Table 1. Overview of Interventions and Study Designs in Evidence Map 1

Interventions

Number of Randomized Controlled

Trials (RCTs)

Interventions Number of

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 (CBT)

6 occupational therapy (OT) 1

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 effectiveness Techniques to lifeStyle (FACETS) program

1 relaxation + psychological training

1

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 programs)

10 strength training 1

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, B-12

1 magnetic field therapy 6

cannabis 1 omega 3 1

cooling therapy 4 tetrahydrocannabinol-Cannabidiol (THC-CBD) oromucosal spray

1

low fat diet + omega 3 supplementation

1

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Interventions

Number of Randomized Controlled

Trials (RCTs)

Interventions Number of

RCTs

Combination (6 studies): RCTs: 2, Controlled Trials: 1, Case Series: 3

exercise, relaxation 1

rehabilitation, repetitive transcranial magnetic stimulation (rTMS)

1

Other (15 studies): RCTs: 11, Controlled Trials: 2, Case Series: 2

rTMS 4

transcranial direct current stimulation (tDCS)

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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.

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Figure 2. Screenshot for Evidence Map 1 (overview)

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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

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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.

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

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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.

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Table 2. Treatments with Sufficient Evidence of Impact on Fatigue

Intervention Impact on Fatigue Translated to the FSS 1-7

Scale

Translated to the MFIS 0-84 Scale

Impact on Quality of Life

Exercise: Aquatic exercise

g=1.66 (based on 3 RCTs25,42,61) Strength: Moderate

2.16 points 24 points g=1.47 (based on 1 RCT25) Strength: Low

Pharmacologic: Paroxetine g=0.84 (based on 1 RCT22) Strength: Low

1.1 points 12 points Inconclusive

Exercise: Combination exercises

g=0.83 (based on 1 RCT45) Strength: Low

1.08 points 12 points g=0.66 (based on 1 RCT45) Strength: Low

Exercise: Yoga

g=0.79 (based on 4 RCTs59-62) Strength: Moderate


Exercise: Supervised aerobic exercise


0.94 points 11 points


Behavioral/Education: Relaxation training

g=0.67 (based on 2 RCTs57,58) Strength: Low


Behavioral/Education: Education on physical activity



Behavioral/Education: Fatigue: Applying Cognitive behavioural and Energy effectiveness Techniques to lifeStyle (FACETS) program

g=0.43 (based on 1 RCT49) Strength: Moderate


CAM: Lofepramine and L-phenylalanine

g=0.36 (based on 1 RCT20) Strength: Moderate


Behavioral/Education: Fatigue management program

g=0.33 (based on 5 RCTs23,30,34,35,37) Strength: Moderate

0.43 points 5 points


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).

19

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.

20

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

21

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

22

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.

23

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.

24

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.

25

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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 Number

Concept Search Statement # Identified

1 MS 'multiple sclerosis'/de OR 'multiple sclerosis':ti OR 'ms':ti OR 'ppms':ti OR 'rrms':ti OR 'spms':ti

140161

2 Fatigue 'fatigue'/de OR 'asthenia'/de OR 'exhaustion'/de OR 'muscle fatigue'/de OR 'lassitude'/de

193902

3 asthenia:ti,ab OR exhaust*:ti,ab OR fatigue*:ti,ab OR lassitude:ti,ab OR legasthenia:ti,ab OR fatigability:ti,ab OR tired*:ti,ab

187421

4 Combine sets – fatigue

#2 OR #3 286132

5 Combine sets – MS fatigue

#1 AND #4 6340

6 Limit by date, English language, human population

5517

7 Drug - Amantadine

‘amantadine’/de OR ‘memantine’/de OR (amantadin* OR adekin 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

25453

48

Set Number


8 Drug - Aminopyridines

‘aminopyridine derivative’/de OR (aminopyridines OR ‘4-aminopyridine’ OR fampridine* OR pymadine* OR ‘VMI-103’ OR amrinone OR Amrinon OR cordemcura OR inocor OR wincoram):ti,ab

8301

9 Drug – aspirin ‘acetylsalicylcic acid’/de OR (aspirin OR acetylsalicylic acid OR 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

192796

10 Drug – bupropion ‘amfebutamone’/de OR (bupropion OR amfebutamone OR 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

16880

49

Set Number


11 Drug – hypnotics and sedatives

'hypnotic sedative agent’/exp or barbituates/exp OR (alprazolam 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

420340

12 Drug – interferon beta

‘beta interferon’/de OR (interferon NEAR/2 beta) 28883

13 Drug - modafinil ‘modafinil’/de OR (Modafinil OR alertec OR modiodal OR Provigil OR sparlon OR vigil OR armodafinil OR attenace OR modasomil OR modavigil OR vigicer):ti,ab

5429

14 Drug – natalizumab

Natalizumab/de OR (natalizumab OR antegren OR tysabri):ti,ab 8225

15 Drug – pemoline Pemoline/de OR (azoxodone OR betanamin OR ceractiv OR 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

1853

16 Drug – prokarin ‘Prokarin’ 9

17 Drug teriflunomide

‘Teriflunomide’ 1854

18 Combine sets – drugs

#7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17

681612

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 #22 AND [Embase]/lim - #24 NOT #23

146

26 Reviews #25 and (review/de OR ((systematic NEAR/2 review*) or (meta NEAR/2 analy*)))

40

50

Set Number


27 #25 NOT (abstract:nc OR annual:nc OR 'book'/exp OR 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)

76

28 #27 NOT #26 37

29 #28 NOT ‘case report’/de 35

Set Number


1 MS 'multiple sclerosis'/de OR 'multiple sclerosis':ti OR 'ms':ti OR 'ppms':ti OR 'rrms':ti OR 'spms':ti

140649

2 Fatigue 'fatigue'/de OR 'asthenia'/de OR 'exhaustion'/de OR 'muscle fatigue'/de OR 'lassitude'/de

194026

3 asthenia:ti,ab OR exhaust*:ti,ab OR fatigue*:ti,ab OR lassitude:ti,ab OR legasthenia:ti,ab OR fatigability:ti,ab OR tired*:ti,ab

190256

4 Combine sets – fatigue

#2 OR #3 287716

5 Combine sets – MS fatigue

#1 AND #4 6348

6 Limit by date, English language, human population

5518

7 CAM – general ‘Dietary supplement’/de OR ‘plant medicinal product’/exp OR ‘medicinal plant’/exp

1371008

8 CAM – carnitine Carnitine/de OR carnitine OR levocarnitine OR (levo NEAR/1 carnitine)

23049

9 CAM – coenzyme Q10

((coenzyme OR ‘co-enzyme’) NEAR/1 Q10) OR ubiquinone OR ubisemiquinone OR ubiten

21678

10 CAM – vitamin A ‘vitamin A’ OR tretinoin OR aquasol OR retinol 60136

11 CAM -Andrographis paniculata

(andrographis NEAR/2 paniculata) OR andrographis/de 1683

12 CAM – sulbutiamine

Thiamine/de OR (sulbutiamine OR viaverm) 19607

13 CAM - ginseng Ginseng/de OR (ginseng OR ‘jen shen’ OR ninjin OR renshen OR schinseng OR shinseng):ti,ab

9978

14 CAM – Acupressure Acupuncture

Acupuncture/exp OR (acupuncture OR pharmacopuncture OR shiatsu OR ‘tui-na’)

45450

15 CAM – cryotherapy

cryotherapy/de OR (cryotherap* OR cryotreatment OR cryogenic OR “cold therapy” OR cryotherm*):ti,ab

23099

16 CAM – mind/body techniques

Meditation/de OR ‘relaxation training’/de OR Meditat*:ti,ab OR (relax* NEAR/2 (therap* OR method* OR technique* OR training))

25671

51

Set Number


17 Devices transcranial magnetic stimulation/exp OR (repetitive NEAR/2 magnetic) OR rTMS OR (transcranial NEAR/2 (direct OR magnetic)) or tDCS or (electrotherapy/de AND (transcranial OR repetitive):ti)

26851

18 Neurofeedback/de OR Neurofeedback:ti,ab OR ((alpha OR brainwave OR EEG OR electroencephalograph* OR electromyograph*) NEAR/2 (feedback OR biofeedback))

4474

19 Self-management self care/exp OR (self NEAR/4 (care OR efficac* OR manag* OR monitor*)):ti

19970

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 #15 OR 20

1708252

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 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)

102

27 #26 and (review/de OR ((systematic NEAR/2 review*) or (meta NEAR/2 analy*)))

38

28 #26 NOT #27 64

29 #28 AND ‘case report’/de - 3 #29 AND (case NEAR/2 series) – 0 #28 NOT #29

61

30 #29 AND [medline]/lim 47

31 #31 NOT #32 14

32 Exclude overlap with PCOR5 drug search strategy

11

National Guideline Clearinghouse

MeSH browse – multiple sclerosis

Search:

S1: “multiple sclerosis”

52

Appendix B. Included and Excluded Interventions

Included Interventions

Pharmacologic Exercise Behavioral/Education CAM Combination Other

Amantidine Modafinil Armodafinil Detroamphetamine +

Amphetamine (Adderall)

Dextroamphetamine (dexedrine)

L-dexamfetamine Methylphenidate 4-aminopyridine

(dalfampridine, fampridine)

L-carnitine Aspirin 3, 4 diaminopyridine

(DAP) Histamine Histamine + Caffeine Paroxetine Buproprion Fluoxetine Sertraline Duloxetine

Aerobic, balance and stretching exercises (including yoga)

Supervised exercise programmes involving moderate progressive resistance training

Aquatic exercise Vestibular

rehabilitation Climbing exercise Treadmill exercise Inspiratory exercise Balance training

(including Falls Prevention Program)

Gait training (including robotic assisted)

Rehabilitation programs (except for cognitive rehab)

Physical Therapy (including use of motor imagery and rhythmic auditory stimulation)

Mindfulness-based training (e.g., meditation)

Cognitive behavioral therapy (CBT)

Group psychotherapy Relaxation therapy

(including progressive muscle relaxation)

Cognitive rehabilitation Neuropsychological

training program Education Energy conservation

programs Fatigue management

programs (self-management, self-care)

Exercise counseling programs (e.g., education or motivational or online)

Online interactive exercise motivational program + Pedometer

Occupational therapy FACETS (Fatigue:

Applying Cognitive Behavioral and Energy Self effectiveness Techniques to lifeStyle)

Electromagnetic field therapy

Cooling therapy Cannabinoids (e.g.,

THC:CBD oromucosal spray)

cannabis lofepramine plus

phenylalanine with B12

magnetic therapy low fat diet with

omega-3 supplementation (or omega-3 supplementation)

Acupuncture

Aerobic, moderate progressive resistance activity combined with CBT

Non-invasive brain stimulation (i.e., transcranial magnetic stimulation, transcranial direct current stimulation)

Continuous positive airway pressure (CPAP)

53

Excluded Interventions

Acupressure Alemtuzumab Andrographis paniculata Angioplasty/venoplasty for central chronic venous insufficiency Art therapy B-alanine Bee venom Biofeedback stress management Biofeedback/Neurofeedback Coenzyme Q/MitoQ Constraint induced movement therapy Cryostimulation D-aspartate Dietary counseling Diet high in omega 3 fatty acids, polyphenols, antioxidants, without refined sugars Dimethyl fumarate Dorsiflexion assisted orthosis Duloxetine Emotion focused therapy Fingolimod Gingko biloba Functional electrical stimulation Ginseng Green tea catechins High flavonoid cocoa High voltage pulsed galvanic stimulation Hippotherapy Hydrotherapy Hyperbaric oxygen

Hypnotherapy Lipoic acid Lisdexamfetamine dimesylate Lithium Low fat plant based diet, low fat diet Low level laser therapy Massage therapy MD 1003 Mechanical focal vibration Melatonin Methylprednisone Modified Paleo diet Motivational interviewing N-acetyl cysteine Naturopathy medicine Neuromuscular taping Peginterferon Beta 1a Pemoline Ponesimide Reflexology Riluzole Rivastigmine Social cognitive treatment Stem cell transplant Sulbutiamine Support groups (web based or face to face) Thinking prompts added to gait training Teriflunomide Tizanidine Transcranial random noise stimulation Vitamin A Vitamin D Week-long educational by physicians

54

Appendix C. Related PCORI‐funded Projects and clinicaltrials.gov records

Table 3. Related PCORI-funded Projects

Author Title Start Date and Projected End Date

NCT Number Study Design

Number of Patients

Category of Intervention

Specific Intervention

Outcomes

Backus, D Comparative Effectiveness Study Telerehab Versus Conventional

July 2018 to Jan 2022

NCT03468868 RCT 500 Exercise Resistance and cardio exercise, supervised vs. home

Timed 25 foot walk, Neuro QOL, Modified Fatigue Impact Scale

Plow MA Comparing the Effectiveness of Fatigue Management Programs for People with MS

Sep 2017 to Sep 2021

NA RCT 610 Behavioral/Education

Managing fatigue course: face-to-face vs. teleconference vs. internet

Fatigue; QOL

Nourbakhsh B, Raj Revirajan N

Comparing Three Medicines to Treat Fatigue in Patients with Multiple Sclerosis (MS)

July 2016 to Sep 2020

NCT03185065 RCT 136 Pharmacologic Amantadine; Modafinil; Methylphenidate; Placebo

Fatigue; QOL; Sleepiness

Braley T, Kratz A

A Randomized Controlled Trial of Telephone-Delivered Cognitive Behavioral Therapy, Modafinil, and Combination Therapy of Both Interventions for Fatigue in Multiple Sclerosis

Sep 2017 to June 2021

NA NR NR Behavioral/Education; Pharmacologic; Combination

Cognitive behavioral therapy; modafinil

Fatigue; depression; disability; sleep disturbance

Rimmer J Comparing Clinic- and Home-Based Exercise Programs to Help Adults with Multiple Sclerosis

July 2016 to Nov 2021

NCT03117881 RCT 820 Exercise In-person supervised exercise; online exercise support

QOL; physical activity; pain; fatigue; balance; endurance; gait; strength

Ehde DM Improving the Quality of Care for Pain and Depression in Persons With Multiple Sclerosis

May 2014 to Mar 2017

NCT02137044 RCT 200 Behavior/Education

Care coordination

Pain; depression; fatigue; hrQOL; delta depression care; delta depression severity; delta pain severity; delta disability; delta satisfaction with care

NA – Not available NR – Not reported

55

Table 4. Related Records in clinicaltrials.gov

NCT Number Title Start Date and Projected End Date

Study Design

Number of Patients

Intervention(s) Outcomes

NCT01611987 The Role of Exercise in Modifying Outcomes for People With Multiple Sclerosis

Sep 2012 to Dec 2018

RCT 240 Supervised aerobic exercise

Oxygen consumption; muscle strength measured with Biodex; 6 Minute Walk test (6MWT); Anaerobic 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 With Multiple Sclerosis: Who Benefits the Most? (MSVR3trial)

Oct 2012 to Nov 2018

RCT 88 Multidisciplinary rehabilitation

Balance (Dynamic Posturography/Computerized Sensory Organization Test); Visual Stability (Dynamic Visual Acuity and Gaze Stabilization Test); Perceived fatigue (Modified fatigue Impact Scale)

NCT01746342 Sleep Apnea in Multiple Sclerosis Positive Airway Pressure Trial

Feb 2013 to Mar 2019

RCT 65 CPAP Fatigue Severity Scale; Fatigue Scale for Motor and 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 Dysfunction and Motor fatigue in Multiple Sclerosis

Apr 2015 to Mar 2019

RCT 30 4-aminopyridine Eye movement assessment; Visual function assessment; Gait assessment; Visual disability assessment; Quality of life assessment

NCT02421731 Robot-assisted Gait Training on Mobility in Severely Disabled Multiple Sclerosis Patients

Feb 2014 to Feb 2018

RCT 98 Robot-assisted gait training

Six-Minute Walking Test ; Berg Balance Scale ; Up and Go Test ; Fatigue Severity Scale ; Modified Ashworth Scale ; Short-Form 36 ; Haemodynamic measurements ; Metabolic measurements by Near infrared spectroscopy ; Circulating biomarkers

NCT02425644 Oral Ponesimod Versus Teriflunomide In Relapsing Multiple Sclerosis

Jun 2015 to May 2019

RCT 1100 Ponesimod vs. terifunomide

Annualized relapse rate (ARR); Time to 12-week 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

56


Study Design

Number of Patients


NCT02440516 Standardized Ambulatory Neurorehabilitation Program for Patients With Multiple Sclerosis

Feb 2016 to Jul 2018

RCT 62 Fatigue management program

Change from baseline in Multiple Sclerosis Impact Scale 29 (MSIS-29); Change from baseline in Coin 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 Multiple Sclerosis

Aug 2016 to Dec 2018

RCT 15 Aquatic exercise Cognition measured by results of standardized neuropsychological tests; fatigue measured by self-report questionnaires; Quality of Life measured by self-report questionnaires

NCT02538094 tDCS and Cognition in Adults With Multiple Sclerosis or Encephalitis

Sep 2014 to Sep 2018

RCT 50 Transcranial direct current stimulation

Cognition; fatigue


57


Study Design

Number of Patients


NCT02583386 Comprehensive Fall Prevention and Detection in Multiple Sclerosis

Apr 2016 to May 2019

RCT 94 Exercise and educational program

Change from Baseline in Self-Reported Falls and Fall-Related Injuries at Completion of Program and 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 Physical Exercises in People With Multiple Sclerosis

Dec 2015 to Jan 2020

RCT 100 Unsupervised aerobic exercise vs. relaxation training

Fatigue; Change in fatigue; Safety (Number of patients with adverse events related to treatment); Change in MS-specific health related quality of life; 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


58


Study Design

Number of Patients


NCT02634567 Attention/Working Memory Rehabilitation in Multiple Sclerosis: A Pilot Project Using Cogmed Working Memory Training

Apr 2016 to Dec 2018

RCT 30 Unsupervised aerobic exercise

Paced Auditory Serial Addition Test; Symbol Digit Modalities Test; Stroop colour word test; Judgement of Line Orientation; Controlled Oral Word Association 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 Training in Patients With Multiple Sclerosis

Feb 2016 to May 2019

RCT 60 Respiratory rehabilitation

Fatigue graded according to EMIF-SEP questionnaire; Sleep disorders graded according to 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 Depression in MS

Feb 2017 to Apr 2019

RCT 400 CBT alone vs. CBT + weekly emails vs. waitlist

Beck Depression Inventory-II; WHO Quality of Life scale (WHO-QOL BREF); Multiple Sclerosis Impact Scale (MSIS); fatigue Scale for Motor and Cognitive Functions (FSMC); Chalder fatigue Scale


59


Study Design

Number of Patients


NCT02870023 How Does Strength Training and Balance Training Affect Gait Function and fatigue in Patients With Multiple Sclerosis?

Jun 2016 to Dec 2018

RCT 90 Resistance training vs. balance training vs. no treatment

Change in gait speed measured by "Six Spot Step Test"; Change in gait speed measured by "Timed 25 Foot Walk"; fatigue; Endurance; Self-evaluated gait function; Temporospatial measures; Balance - static; Balance - functional; Balance - confidence; Strength

NCT02874677 A Reeducation Program to Effort to Improve the Walking of Multiple Sclerosis Patients

Oct 2017 to May 2020


Distance estimated by the 6 minute Walk Test; Walking speed measured by the timed 25-ft walk test (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 Acupuncture on Mobility And Quality of Life in Multiple Sclerosis

Jun 2017 to Jul 2019

RCT 30 Acupuncture Fatigue severity scale; Medical Outcomes Study Pain Effects Scale; Gait measured by 6-minute walk test; Balance measured by 25-foot walk test

NCT03244696 Behavior and Activity Monitoring in MS

Nov 2017 to Jan 2020

RCT 200 Step count monitoring vs. water tracking

Change in Cognitive Performance on Minimal Assessment of Cognitive Function in Multiple 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 Sclerosis

Apr 2018 to Sep 2020

RCT 166 Education on physical activity vs. supervised aerobic exercise

Change in Annual Relapse Rate (ARR); Percentage brain volume change; Multiple Sclerosis Functional Composite (MSFC); Expanded Disability Status Scale (EDSS) score


60


Study Design

Number of Patients


NCT03353974 Video Games Therapy on Balance and Cognitive Functions in Mild to Moderate Impaired Multiple Sclerosis Patients.

Dec 2017 to Dec 2018

RCT 40 Video game therapy vs. balance platform therapy

Timed Up and Go (TUG) test; Four Square Step Test (FSST); Functional Reach Test (FRT); Berg Balance Scale (BBS); Dynamic Gait Index (DGI); Modified 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 Sclerosis

Dec 2017 to Dec 2018

RCT 30 Transcranial direct current stimulation + rehabilitation vs. sham + rehabilitation

Numeric Rating Scale (NRS); Short Form McGill Pain Questionnaire (SF-MPQ); Brief Pain Inventory (BPI); Pain Catastrophizing Scale (PCS); Coping Strategies Questionnaire (CSQ); Beck Depression Inventory II (BDI-II); MS Quality of Life - 54 (MSQOL-54); fatigue 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 Jan 2019


Change in measure of quality of life; Change in 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)


61


Study Design

Number of Patients


NCT03471338 Neuropsychological Management of Multiple Sclerosis: Benefits of a Computerised Semi-autonomous At-home Cognitive Rehabilitation Programme

Oct 2017 to Dec 2019

RCT 40 Cognitive training

Efficacy of cognitive rehabilitation on quality of life at short term; Efficacy of cognitive rehabilitation on quality of life at long term; Efficacy of cognitive rehabilitation on self-esteem at short term; Efficacy of 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.


62


Study Design

Number of Patients


NCT03490240 Project BIPAMS: Behavioral Intervention for Physical Activity in Multiple Sclerosis

Mar 2018 to Mar 2021

RCT 280 General education vs. education on physical activity

Change of Physical Activity levels through Accelerometery from baseline at 6 and 12 months; Change of Physical Activity levels through the Godin 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 in Non-disabled MS People: Assessment and Potential Therapeutic Interventions

Apr 2018 to Jun 2020


Change in Six Minutes Walking Test; Change in Instrumented variables; the Twelve-Item Walking Scale; the Twenty-five-foot walking test; The fatigue Severity Scale; the Nine hole peg test


63


Study Design

Number of Patients


NCT03501342 Effects of Immersive Virtual Reality on Balance, Mobility, and fatigue in Patients With Multiple Sclerosis

Apr 2018 to Jun 2020

RCT 30 Virtual reality vs. dynamic balance training vs. no treatment

Berg Balance Scale; Timed Up and Go Test; Modified Sensory Organization Test; One-leg standing duration; Activities-specific Balance Confidence; fatigue Severity Scale; fatigue Impact Scale

NCT03521557 Gaze and Postural Stability in Multiple Sclerosis

May 2018 to Sep 2020

RCT 50 Gaze and postural stability exercises

Dizziness Handicap Inventory; Dizziness Handicap Inventory Follow-up; Activity Specific Balance 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 Walking With Blood Flow Restriction on Functional Capacity in Multiple Sclerosis

May 2018 to Jul 2021

RCT 40 Supervised aerobic exercise interval walking vs. Supervised aerobic exercise conventional

Timed 25-foot Walk test; 6-Minute Walking Test; Berg Balance Scale; 5-time Sit-to-Stand test; Multiple Sclerosis Impact Scale; fatigue Severity Scale; Short Form Health Survey 36

NCT03638739 Exercise and Brain Health in MS Aug 2018 to Jun 2019


Change in Perceived fatigue; Change in 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

64

Appendix D. Evidence Tables

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

Reference Intervention Category

Type of Intervention Specific Intervention Total Patients in Study

Number Assigned to This Treatment Group

US or Non-US Study

van den Akker et al. (2017)38

Behavioral/Education Cognitive behavioral therapy (CBT)

CBT 91 44 Non-US

Kiropoulos et al. (2016)46 Behavioral/Education Cognitive behavioral therapy

CBT 30 15 Non-US

van Kessel et al. (2008)64 Behavioral/Education Cognitive behavioral therapy

CBT 72 35 Non-US

Mohr et al. (2003)65 Behavioral/Education Cognitive behavioral therapy

CBT 71 23 US

Clancy et al. (2015)79 Behavioral/Education Cognitive behavioral therapy

CBT 11 11 Unknown

Pöttgen et al. (2015)80 Behavioral/Education Cognitive behavioral therapy

CBT 27 27 Unknown

Wendebourg et al. (2014)81 Behavioral/Education Cognitive behavioral therapy

CBT (group) 16 16 Non-US

Mohr et al. (2007)82 Behavioral/Education Cognitive behavioral therapy

CBT (telephone) 127 62 US

Fischer et al. (2013)83 Behavioral/Education Cognitive behavioral therapy

Cognitive behavioral therapy (online) 90 45 Non-US

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 assisted)

62 30 Non-US

Pusswald et al. (2014)91 Behavioral/Education Cognitive training Neuropsychological training program (computer based)

40 20 Non-US

Vaughan et al. (2013)84 Behavioral/Education Cognitive training Verbal list learning alternating with rest (pacing) 29 9 Non-US

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

65




US or Non-US Study

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 by OT students

NR NR US

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 program

Energy conservation management program 86 42 Non-US

Garcia et al. (2011)100 Behavioral/Education Energy conservation program


Mathiowetz et al. (2005)101 Behavioral/Education Energy conservation program

Energy conservation management program 169 78 US

Vanage et al. (2003)102 Behavioral/Education Energy conservation program


Mathiowetz et al. (2001)103 Behavioral/Education Energy conservation program


Sauter et al. (2008)104 Behavioral/Education Energy conservation program


Finlayson et al. (2005)105 Behavioral/Education Energy conservation program


Thomas et al. (2013)49 Behavioral/Education FACETS (CBT + energy conservation)

FACETS (CBT + energy conservation) 164 84 Non-US

Jeanette et al. (2017)106 Behavioral/Education FACETS (CBT + energy conservation)

FACETS (CBT + energy conservation) 11 11 Non-US

Hugos et al. (2010)35 Behavioral/Education Fatigue management program

Fatigue management program 41 21 US

Kos et al. (2007)23 Behavioral/Education Fatigue management program

Fatigue management program 51 51 Non-US


66




US or Non-US Study

Horvat et al. (2013)107 Behavioral/Education Fatigue management program


Turpin et al. (2015)108 Behavioral/Education Fatigue management program


Poettgen et al. (2015)109 Behavioral/Education Fatigue management program

Fatigue management program (online) 275 137 Non-US

Finlayson et al. (2011)34 Behavioral/Education Fatigue management program

Fatigue management program (teleconference) 190 94 US

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 training

Psychological training, muscle relaxation 60 30 Non-US

Boosman et al. (2011)118 Behavioral/Education Self-management program

Educational program on balancing capacity and load in daily activities

43 43 Non-US

Anderson et al. (2017)119 Behavioral/Education Self-management program

Self-management program 21 21 Non-US

Mulligan et al. (2015)120 Behavioral/Education Self-management program


Sahebalzamani et al. (2012)121

Behavioral/Education Self-management program



67




US or Non-US Study

Navipour et al. (2006)122 Behavioral/Education Self-management program


Hugos et al. (2017)123 Behavioral/Education Self-management program

Self-management program (group) 40 20 Unknown

Kos et al. (2016)116 Behavioral/Education Self-management program

Self-management program (occupational therapy) 31 17 Non-US

van Kessel et al. (2016)124 Behavioral/Education Self-management program

Self-management program (online) 39 20 Non-US

Moss-Morris et al. (2012)36 Behavioral/Education Self-management program


Ghahari et al. (2010)30 Behavioral/Education Self-management program


Jongen et al. (2015)125 Behavioral/Education Self-management program

Self-management program (online) 56 56 Unknown

van et al. (2016)124 Behavioral/Education Self-management program

Self-management program (online) + email support

39 19 Non-US

Ehde et al. (2015)70 Behavioral/Education Self-management program

Self-management program (telephone) 163 75 US

Ehde et al. (2015)70 Behavioral/Education Self-management program

Self-management program (telephone) 163 88 US

Louie et al. (2015)126 Behavioral/Education Self-management program

Self-management program (weekly exercise + education)

23 12 Non-US

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, L-phenylalanine, B-12

Lofepramine, L-phenylalanine, and intramuscular vitamin B-12

138 69 Non-US

Corey-Bloom et al. (2012)130

CAM Cannabis Smoked cannabis 37 37 US

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. (2005)137

CAM Low fat diet + omega 3 Low fat diet with omega 3 fatty acid supplementation

31 16 US


68




US or Non-US Study

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 spray

THC-CBD oromucosal spray 43 43 Non-US

Vermersch et al. (2016)143 CAM THC-CBD oromucosal spray

THC-CBD oromucosal spray 433 433 Non-US

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 relaxation techniques

20 10 Non-US

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 stimulation

19 19 US

Bisht et al. (2014)148 Combination Exercise, special diet, meditation

Exercise, electrical stimulation, meditation, massage, paleolithic diet

10 10 US

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. (2014)152

Exercise Aerobic exercise Aerobic exercise 90 20 Unknown

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


69




US or Non-US Study

Ahmadi et al. (2013)158 Exercise Aerobic exercise Treadmill exercise 31 10 Non-US

van den Berg et al. (2006)159

Exercise Aerobic exercise Treadmill exercise 19 19 Non-US

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), recumbent stepping

12 6 US

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. (2013)167

Exercise Aquatic exercise Aquatic therapy (Ai chi) 29 11 Non-US

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


70




US or Non-US Study

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) + In Person PT

30 10 US

Fjeldstad et al. (2016)184 Exercise Exercise Exercise program (home based) + Remote PT supervision

30 10 US

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 physiotherapy

112 36 Non-US

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 ergometry)

37 18 Non-US

Sangelaji et al. (2014)45 Exercise Exercise (other) Exercise therapy (aerobic, strengthening, balancing and stretching exercises)

59 39 Non-US

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


71




US or Non-US Study

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 expiratory)

21 21 US

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 (supervised)

120 60 Non-US

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 assisted)

Gait training (robot assisted) 50 25 Non-US

Straudi et al. (2016)68 Exercise Gait training (robot assisted)


Gandolfi et al. (2014)67 Exercise Gait training (robot assisted)


Venturi et al. (2014)208 Exercise Gait training (robot assisted)


Venturini et al. (2011)209 Exercise Gait training (robot 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


72




US or Non-US Study

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. (2013)167

Exercise Pilates Pilates 29 18 Non-US

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 methylprednisolone

39 19 Non-US

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


73




US or Non-US Study

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 based)

71 36 Non-US

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 induced work (RENEW)

22 11 US

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. (2014)152

Exercise Yoga Yoga 90 20 Unknown

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


74




US or Non-US Study

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 supervised)

20 10 US

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), remotely supervised

25 25 US

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


75




US or Non-US Study

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. (2012)280

Pharmacologic Amantidine Amantidine 52 52 Unknown

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 Research Group (1987)283

Pharmacologic Amantidine Amantidine 115 115 Non-US

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. (2017)39

Pharmacologic Aspirin Aspirin 121 61 Non-US

Shaygannejad et al. (2012)280

Pharmacologic Aspirin Aspirin 52 52 Unknown

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


76




US or Non-US Study

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. (2016)298

Pharmacologic Modafinil Modafinil 17 17 US

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.

77

Table 6. Fatigue And Quality of Life Data for Evidence Map 2: Pharmacologic Interventions

Trial Group 1 Specific Treatment

Group 2 Specific Inactive Treatment

Hedges' g (95% CI)

Outcome (Instrument)

Single Study Finding

Group 1 Baseline Mean (SD)

Group 1 Outcome Mean (SD) (N at Follow-up)



Rossini (2001)19

4-AP Placebo 0.38 (-0.19 to 0.95)

Fatigue (FSS) Inconclusive 5.32 (SD: NR)

4.64 (SD:NR) (N=27)

4.9 (SD: NR)

4.61 (SD:NR) (N=22)

Krupp (1995)21 Amantadine Placebo 0.2 (-0.28 to 0.69)

Fatigue (FSS) Inconclusive 5.61 (SD: 0.95)

5.16 (SD:1.22) (N=31)

5.63 (SD: 0.89)

5.4 (SD:1.18) (N=35)

Krupp (1995)21 Amantadine Placebo 0.41 (-0.08 to 0.9)

Fatigue (MS-FS) Inconclusive 4.9 (SD: 1.225)

4.4 (SD:1.67) (N=31)

4.69 (SD: 0.947)

4.72 (SD:1.183) (N=35)

Sadeghi-Naini (2017)39

Aspirin Placebo 0.06 (-0.33 to 0.45)

Fatigue (FSS) Inconclusive 37.2 (SD: NR)

31 (SD:NR) (N=51)

41 (SD: NR)

37.4 (SD:NR) (N=49)

Sadeghi-Naini (2017)39

Aspirin Placebo 0.04 (-0.35 to 0.43)

Fatigue (MFIS total) Inconclusive 38.6 (SD: NR)

32 (SD:NR) (N=51)

42.7 (SD: NR)

37.5 (SD:NR) (N=49)

Moller (2011)55 Modafinil Placebo 0.38 (0 to 0.76)

Fatigue (FSS) Favors Modafinil

6.01 (SD: 0.75)

5.25 (SD:1.24) (N=55)

5.8 (SD: 0.76)

5.42 (SD:1) (N=55)

Moller (2011)55 Modafinil Placebo 0.18 (-0.2 to 0.55)

Fatigue (MFIS) Inconclusive 54.75 (SD: 13.32)

45.3 (SD:16.3) (N=55)

51.2 (SD: 11.8)

44.3 (SD:15.2) (N=55)

Moller (2011)55 Modafinil Placebo -0.08 (-0.45 to 0.3)

QOL (Hamburg QOL Questionnaire in MS [higher scores are WORSE])

Inconclusive 12.1 (SD: 2.44)

11.49 (SD:3.29) (N=55)

11.86 (SD: 2.52)

11.04 (SD:2.52) (N=55)

Ehde (2008)22 Paroxetine No treatment 0.84 (0.17 to 1.51)

Fatigue (MFIS) Favors paroxetine

57.2 (SD: 14.1)

39.3 (SD:14.8) (N=17)

56.7 (SD: 12.6)

52.1 (SD:18.3) (N=19)

Ehde (2008)22 Paroxetine No treatment -0.3 (-0.95 to 0.35)

QOL (SF-36 physical functioning)


36.4 (SD:12.3) (N=17)

36 (SD: 11.4)

35.5 (SD:13.3) (N=18)

FSS- Fatigue Severity Scale MFIS – Modified Fatidue Impact Scale NR – Not reported QOL – Quality of life SD – Standard deviation

78

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



Hedges' g (95% CI)







Comments

Kooshiar (2015)25

Aquatic therapy Usual care 0.65 (0.01 to 1.3)

Fatigue (FSS) Favors aquatic exercise

41.75 (SD: 8.33)

36.06 (SD:12.2) (N=18)

38.33 (SD: 9.01)

39.14 (SD:8.1) (N=19)

Razazian (2016)61

Aquatic exercise Usual care 1.9 (1.12 to 2.67)

Fatigue (FSS) Favors aquatic exercise

48.72 (SD: 11.46)

25.28 (SD:11.71) (N=18)

39.56 (SD: 14.68)

41.22 (SD:13.52) (N=18)

Kooshiar (2015)25


Fatigue (MFIS) Favors aquatic exercise

43.81 (SD: 14.87)

32.56 (SD:16.07) (N=18)

41.29 (SD: 12.53)

42 (SD:12.15) (N=19)

Kargarfard (2017)42

Aquatic exercise Usual care 2.36 (1.47 to 3.25)

Fatigue (MFIS) Favors aquatic exercise

43.1 (SD: 14.6)

32.8 (SD:5.9) (N=17)

44.5 (SD: 9.3)

61 (SD:8.2) (N=15)

Kooshiar (2015)25


QOL (Multicultural Quality of Life Index (MQLIM))

Favors aquatic exercise

63.13 (SD: 13.02)

80.06 (SD:11.53) (N=18)

65.48 (SD: 9.74)

66.52 (SD:6.22) (N=19)

Tarakci (2013)27

Group exercise led by physical therapist

Monthly phone call from a neurologist

1.41 (0.97 to 1.85)

Fatigue (FSS) Favors group exercise led by physical therapist

39.27 (SD: 7.19)

31.01 (SD:7.24) (N=51)

39.84 (SD: 8.44)

43.13 (SD:9.66) (N=48)

Garrett (2013)62

Exercise led by physiotherapist or fitness instructor

No treatment 0.47 (0.14 to 0.8)

Fatigue (MFIS total)

Favors supervised exercise

(SD: NR)

(SD:NR) (N=63)

(SD: NR)

(SD:NR) (N=67)

Used reported CIs of individual group change scores to calculate Hedges' g

Oken (2004)60

Exercise stationery bike

Waitlist 0.24 (-0.43 to 0.91)

Fatigue (Multi-dimensional Fatigue Inventory [MFI])

Inconclusive 13.2 (SD: 4)

12.1 (SD:2.8) (N=15)

15.2 (SD: 3.4)

14.9 (SD:3) (N=20)

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

79



Hedges' g (95% CI)







Comments

Garrett (2013)62



QOL (MSIS-29 Physical [higher scores are WORSE])

Favors supervised exercise

(SD: NR)

(SD:NR) (N=67)

(SD: NR)

(SD:NR) (N=49)


Tarakci (2013)27

Group exercise led by physical therapist


0.25 (-0.15 to 0.64)

QOL (MusiQOL) Inconclusive 74.41 (SD: 9.2)

76.39 (SD:9.53) (N=51)

73.42 (SD: 9.73)

73.02 (SD:10.3) (N=48)

Oken (2004)60


Waitlist -0.08 (-0.75 to 0.59)


Inconclusive 62 (SD: 25.9)

60 (SD:27.9) (N=15)

58.1 (SD: 19)

58.1 (SD:23.3) (N=20)

Petajan (1996)18

Exercise No treatment NR Fatigue (FSS) Inconclusive NR NR NR NR Only reported that the between group difference was not significant

Mokhtarzade (2017)40

Aerobic exercise No treatment 0.72 (0.09 to 1.35)

Fatigue (FSS) Favors exercise

3.45 (SD: 0.87)

2.67 (SD:1.28) (N=22)

3.51 (SD: 1.11)

3.56 (SD:1.16) (N=18)

Hasanpour (2016)59

Exercise walking No treatment 1.56 (0.86 to 2.26)

Fatigue (Rhoten Fatigue Scale)

Favors exercise

4.9 (SD: 1.333)

2.55 (SD:0.944) (N=20)

3.8 (SD: 1.641)

3.55 (SD:1.234) (N=21)

Mokhtarzade (2017)40

Aerobic exercise No treatment 0.82 (0.18 to 1.46)

QOL (MSQOL-54)

Favors aerobic exercise

54.21 (SD: 14.63)

63.78 (SD:12.47) (N=22)

52.2 (SD: 12.91)

50.87 (SD:11.2) (N=18)

Hasanpour (2016)59

Exercise walking No treatment 1.42 (0.73 to 2.11)


Favors exercise

44.14 (SD: 7.38)

52.12 (SD:9.87) (N=20)

42.2 (SD: 8.3)

38.12 (SD:7.88) (N=21)

Petajan (1996)18

Exercise No treatment 1.12 (0.49 to 1.74)

QOL (SIP total [higher score is worse])

Favors exercise

94.4 (SD: 29.6)

68.5 (SD:24.7) (N=21)

65.9 (SD: 19)

65.7 (SD:18.1) (N=25)


80



Hedges' g (95% CI)







Comments

Dalgas (2010)33

Progressive resistance training

Usual care 0.4 (-0.29 to 1.1)


4.9 (SD:1.12) (N=16)

5.5 (SD: 0.9)

5.1 (SD:1.63) (N=15)

Dodd (2011)51

Exercise resistance training

Usual care plus attention and social program

-0.06 (-0.54 to 0.42)

Fatigue (MFIS) Inconclusive 41.9 (SD: 14)

39 (SD:14.7) (N=36)

40 (SD: 15.8)

36.2 (SD:16.2) (N=31)

Dalgas (2010)33

Progressive resistance training

Usual care 0.69 (-0.01 to 1.4)



45.3 (SD:7.23) (N=16)

42.6 (SD: 7.32)

41.5 (SD:5.96) (N=15)

Dodd (2011)51

Exercise resistance training

Usual care plus attention and social program

-0.2 (-0.68 to 0.28)

QOL (WHOQOL-BREF)


3.7 (SD:1.1) (N=36)

3.9 (SD: 1)

4 (SD:1) (N=31)

Razazian (2016)61

Yoga Usual care 1.81 (1.05 to 2.57)

Fatigue (FSS) Favors yoga 38.94 (SD: 13.63)

16.22 (SD:9.6) (N=18)

39.56 (SD: 14.68)

41.22 (SD:13.52) (N=18)

Garrett (2013)62

Yoga No treatment 0.42 (0.04 to 0.79)


Favors yoga NR NR NR NR Used reported CIs of individual group change scores to calculate Hedges' g

Oken (2004)60

Yoga Waitlist 0.44 (-0.17 to 1.05)

Fatigue (Multidimensional Fatigue Inventory [MFI])


13 (SD:2.9) (N=22)

15.2 (SD: 3.4)

14.9 (SD:3) (N=20)

Hasanpour (2016)59


Fatigue (Rhoten Fatigue Scale)

Favors yoga 4.75 (SD: 1.712)

3.35 (SD:0.812) (N=20)

3.8 (SD: 1.641)

3.55 (SD:1.234) (N=21)


81



Hedges' g (95% CI)







Comments

Garrett (2013)62

Yoga No treatment 0.28 (-0.09 to 0.65)


Inconclusive (SD: NR)

(SD:NR) (N=63)

(SD: NR)

(SD:NR) (N=49)


Hasanpour (2016)59



Favors yoga 40.1 (SD: 7.16)

50.14 (SD:11.15) (N=20)

42.2 (SD: 8.3)

38.12 (SD:7.88) (N=21)

Oken (2004)60

Yoga Waitlist 0.09 (-0.52 to 0.69)



61 (SD:31.6) (N=22)

58.1 (SD: 19)

58.1 (SD:23.3) (N=20)

Rietberg (2014)26

Multidisciplinary rehabilitation

Nurse consultation

0.17 (-0.43 to 0.76)

Fatigue (CIS-20R)


81 (SD:9.5) (N=21)

79 (SD: 13)

80 (SD:11) (N=23)

Nedeljkovic (2016)31

Rehabilitation + high-dose methylpred-nisolone

High-dose methylpred-nisolone

0.35 (-0.27 to 0.97)


36.6 (SD:21.1) (N=19)

41.1 (SD: 12.9)

40.6 (SD:15.9) (N=20)

Rietberg (2014)26


Nurse consultation

0.4 (-0.2 to 1)

Fatigue (MFIS) Inconclusive 43 (SD: 18.75)

42 (SD:11) (N=21)

36 (SD: 14.5)

42 (SD:21) (N=23)

Rietberg (2014)26


Nurse consultation

0.3 (-0.29 to 0.9)


Inconclusive 53 (SD: 20)

45 (SD:19.5) (N=21)

43 (SD: 19)

41 (SD:21) (N=23)

Carter (2014)44

Supervised exercise and CBT

Usual care 0.23 (-0.17 to 0.62)

Fatigue (MFIS) Inconclusive 45 (SD: 17)

39.6 (SD:16.6) (N=49)

42.8 (SD: 15.7)

41.3 (SD:18.8) (N=50)

Carter (2014)44

Supervised exercise and CBT

Usual care 0.46 (0.06 to 0.86)

QOL (MSQoL-54 Overall)

Favors supervised exercise with CBT

58.3 (SD: 21.8)

65.9 (SD:20.1) (N=49)

62.4 (SD: 20.3)

60.4 (SD:21.1) (N=50)


82



Hedges' g (95% CI)







Comments

Sangelaji (2014)45

Combination exercises (aerobic, balancing, strengthening)

“Control group”; specific treatment not reported

0.83 (0.26 to 1.4)

Fatigue (FSS) Favors combination exercises

38.36 (SD: NR)

33.56 (SD:NR) (N=35)

33.87 (SD: NR)

39.27 (SD:NR) (N=20)

Sangelaji (2014)45

Combination exercises (aerobic, balancing, strengthening)

“Control group”; specific treatment not reported

0.66 (0.1 to 1.23)

QOL (MS-QoL-54)

Favors combination exercises

58.46 (SD: NR)

60.56 (SD:NR) (N=35)

66.33 (SD: NR)

57.53 (SD:NR) (N=20)


83

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



Hedges' g (95% CI)







Comments

Pilutti (2014)48

Behavioral intervention to encourage physical activity via education

Waitlist 0.64 (0.18 to 1.1)

Fatigue (FSS) Favors behavioral intervention

(SD: NR)

4.6 (SD:1.22) (N=37)

(SD: NR)

5.4 (SD:1.25) (N=39)

Motl (2017)56

Education with website and video chats

Waitlist 0.5 (-0.09 to 1.1)

Fatigue (FSS) Inconclusive 5.1 (SD: 1)

4.4 (SD:0.96) (N=23)

4.9 (SD: 1.2)

4.9 (SD:0.89) (N=20)

Turner (2016)28

Telephone counseling

Self-directed education

0.71 (0.2 to 1.22)

Fatigue (MFIS) Favors telephone counseling

53.78 (SD: 14.6)

44.73 (SD:15.2) (N=30)

49.65 (SD: 14.6)

49.7 (SD:15.22) (N=33)

Motl (2017)56

Education with website and video chats

Waitlist 0.75 (0.13 to 1.37)

Fatigue (MFIS) Favors education

44.5 (SD: 14.2)

36.8 (SD:10.55) (N=23)

42.7 (SD: 17.5)

44.7 (SD:10.29) (N=20)

Pilutti (2014)48


Waitlist 0.43 (-0.02 to 0.89)



35.7 (SD:10.9) (N=37)

(SD: NR)

40.5 (SD:11.2) (N=39)

Pilutti (2014)48


Waitlist 0.44 (-0.01 to 0.9)

QOL (MSIS-29 Physical (higher scores are WORSE))


29.1 (SD:9.1) (N=37)

(SD: NR)

33.2 (SD:9.4) (N=39)

Afrasiabifar (2016)43

Oren's self-care model (education)


Fatigue (FSS) Favors Oren's model

6.22 (SD: 2.06)

1.68 (SD:2.171) (N=31)

6.04 (SD: 2.227)

6.45 (SD:1.448) (N=31)

Shinto (2008)52

Education Usual care -0.13 (-0.83 to 0.57)

Fatigue (MFIS) Inconclusive (SD: NR)

(SD:NR) (N=)

(SD: NR)

(SD:NR) (N=)


84



Hedges' g (95% CI)







Comments

Shinto (2008)52

Education - series of 8 visits with MS nurse to go over information in a MS pamphlet

Usual care 0.3 (-0.4 to 1.01)



(SD:NR) (N=NR)

(SD: NR)

(SD:NR) (N=NR)

Blikman (2017)37

Energy conservation management

Education with nurse consultations

0.22 (-0.25 to 0.7)

Fatigue (CIS-20R Fatigue)


40.9 (SD:9.6) (N=34)

43.6 (SD: 7.1)

42.1 (SD:8.9) (N=35)

Thomas (2013)49

FACETS program (CBT, social cognitive, energy effectiveness, self-management)

Usual care 0.43 (0.1 to 0.76)

Fatigue (Global Fatigue Severity [GFS])

Favors FACETS

5.6 (SD: 0.98)

5.26 (SD:1.03) (N=70)

5.61 (SD: 1.09)

5.66 (SD:0.93) (N=74)

Thomas (2013)49

FACETS program (CBT, social cognitive, energy effectiveness, self-management)

Usual care 0.11 (-0.22 to 0.43)

QOL (MSIS [higher scores are worse])


44.9 (SD:19.2) (N=70)

43.9 (SD: 17.6)

43 (SD:17.3) (N=74)

Ghahari (2010)30

Online education with interactive components

Usual care 0.21 (-0.27 to 0.69)

Fatigue (Fatigue Impact Scale [FIS])


64.29 (SD:34.25) (N=34)

76.36 (SD: 32.16)

67.64 (SD:36.69) (N=33)

Finlayson (2011)34

Fatigue management program via tele-conference

Waitlist 0.61 (0.5 to 0.72)

Fatigue (Fatigue Impact Scale [FIS] Physical [FIS total was not reported])

Favors fatigue management via tele-conference

(SD: NR)

(SD:NR) (N=68)

(SD: NR)

(SD:NR) (N=70)


85



Hedges' g (95% CI)







Comments

Finlayson (2011)34


Waitlist 0.33 (0.3 to 0.36)

Fatigue (FSS) Favors fatigue management via tele-conference

(SD: NR)

(SD:NR) (N=68)

(SD: NR)

(SD:NR) (N=70)

Hugos (2010)35

Fatigue management program (6 weeks)

Usual care -0.07 (-0.76 to 0.63)


49.13 (SD:11.3) (N=15)

51.53 (SD: 11.3)

47.4 (SD:11.3) (N=15)

Kos (2007)23

fatigue management program (4 weeks)

Education (not related to fatigue)

NR Fatigue (MFIS) Inconclusive NR NR NR NR Only reported different between groups in proportion of patients with >=10 point change in MFIS (no CI's reported, just effect size)

Hugos (2010)35

Fatigue management program (6 weeks)

Usual care 0.2 (-0.5 to 0.9)

Fatigue (MFIS) Inconclusive 44 (SD: 13.4)

39.79 (SD:13.4) (N=15)

45.87 (SD: 12.97)

44.4 (SD:12.97) (N=15)

Blikman (2017)37

Energy conservation management


0.11 (-0.36 to 0.58)



41.4 (SD:13.9) (N=34)

42.7 (SD: 14.4)

40.6 (SD:16.7) (N=35)

Ghahari (2010)30

Online education with interactive components

Usual care 0.05 (-0.42 to 0.53)

QOL (Personal Well Being Scale)


60.92 (SD:20.91) (N=34)

58.74 (SD: 19.3)

61.36 (SD:20.07) (N=33)

Finlayson (2011)34


Waitlist 0.27 (0.17 to 0.37)

QOL (SF-36 physical function (SF-36 total was not reported))

Favors fatigue management via tele-conference

NR NR NR NR Cohen’s D from the authors’ Table 5


86



Hedges' g (95% CI)







Comments

Blikman (2017)37

Individual energy conservation management with occupational therapist


0.25 (-0.22 to 0.73)



55.4 (SD:25.7) (N=34)

59.2 (SD: 26.4)

54 (SD:28.5) (N=35)

Moss-Morris (2012)36

CBT (internet based)


Fatigue (Chalder Fatigue scale)

Favors CBT 21.39 (SD: 4.3)

12.39 (SD:6.84) (N=20)

21.53 (SD: 3.62)

19.57 (SD:5.2) (N=16)

van den Akker (2017)38

CBT Nurse consultations

-0.08 (-0.54 to 0.38)

Fatigue (CIS-20R Fatigue)


38.9 (SD:9.7) (N=39)

44.2 (SD: 6)

39.5 (SD:9) (N=35)



0 (-0.45 to 0.45)


5 (SD:0.9) (N=39)

5.5 (SD: 0.8)

5.1 (SD:0.9) (N=37)

Moss-Morris (2012)36

CBT (internet based)


Fatigue (MFIS) Favors CBT 13.17 (SD: 3.81)

9 (SD:3.75) (N=21)

12.69 (SD: 3.89)

12.88 (SD:3.89) (N=16)



-0.31 (-0.76 to 0.14)



42.5 (SD:12.2) (N=39)

47.7 (SD: 9.6)

39.1 (SD:13.8) (N=37)

Kiropoulos (2016)46

CBT Usual care 0.97 (0.23 to 1.71)

Fatigue (MFIS-5) Favors CBT 12.13 (SD: 3.58)

8.06 (SD:3.03) (N=15)

12.26 (SD: 3.84)

11.93 (SD:4.38) (N=15)

Kiropoulos (2016)46

CBT Usual care 0.51 (-0.2 to 1.22)

QOL (MSQOL-54)


63.32 (SD:17.25) (N=15)

43.28 (SD: 17.63)

49.33 (SD:21.32) (N=15)



0.09 (-0.36 to 0.54)



55.9 (SD:22.3) (N=39)

62.2 (SD: 20.4)

60.3 (SD:22) (N=37)

Rosti-Otajarvi (2013)54

Outpatient neuropsycho-logical rehabilitation

No treatment 0.19 (-0.27 to 0.65)

Fatigue (FSMC total score)


59 (SD:17.7) (N=50)

66.3 (SD: 15.6)

64.4 (SD:16.5) (N=28)


87



Hedges' g (95% CI)







Comments

Pérez-Martín (2017)41

Cognitive rehabilitation training

Received a book containing guidelines and general advice, and were contacted once a week

0.21 (-0.29 to 0.71)


30.51 (SD:20.22) (N=30)

28.89 (SD: 21.79)

29.21 (SD:21.94) (N=32)

De Giglio (2015)53

Cognitive training (video console)

Usual care 0.54 (-0.13 to 1.21)


28.5 (SD:14.56) (N=18)

32.69 (SD: 14.095)

32.69 (SD:14.91) (N=16)

Rosti-Otajarvi (2013)54

Outpatient neuropsycho-logical rehabilitation

No treatment 0.01 (-0.45 to 0.47)



22.9 (SD:15.5) (N=50)

26.1 (SD: 17.2)

24.2 (SD:14) (N=28)

Pérez-Martín (2017)41

Cognitive rehabilitation training

Received a book containing guidelines and general advice, and were contacted once a week

0.88 (0.36 to 1.4)

QOL (MSQoL-54 Physical)

Favors cognitive rehabilitation training

46.43 (SD: 17.83)

52.99 (SD:19.2) (N=30)

63.75 (SD: 17.27)

63.24 (SD:16.98) (N=32)

De Giglio (2015)53

Cognitive training (video console)

Usual care -0.23 (-0.89 to 0.43)

QOL (MSQOL-54 Physical Health Composite)


62.7 (SD:11.84) (N=18)

57.04 (SD: 14.67)

62.72 (SD:14.84) (N=16)

Bogosian (2015)47

Mindfulness (online)

Usual care -0.24 (-0.91 to 0.43)


43.87 (SD:13.39) (N=15)

48.29 (SD: 12.24)

49.08 (SD:12.43) (N=18)

Grossman (2010)24

Mindfulness based intervention

Usual care 0.57 (0.23 to 0.91)

Fatigue (MFIS) Favors mindfulness

35.15 (SD: 16.68)

(SD:NR) (N=72)

30.28 (SD: 14.98)

(SD:NR) (N=67)


Bogosian (2015)47

Mindfulness (online)

Usual care 0.23 (-0.46 to 0.91)

QOL (Euro QOL [EQ-5D])


0.51 (SD:0.37) (N=14)

0.48 (SD: 0.33)

0.5 (SD:0.29) (N=18)


88



Hedges' g (95% CI)







Comments

Grossman (2010)24

Mindfulness based intervention

Usual care 0.41 (0.07 to 0.75)

QOL (Hamburg QOL Questionnaire in MS [higher scores are WORSE])

Favors mindfulness

2.22 (SD: 0.67)

(SD:NR) (N=72)

2.13 (SD: 0.6)

(SD:NR) (N=67)


Nazari (2015)57

Relaxation training

Usual care 0.47 (-0.09 to 1.03)


4.37 (SD:0.78) (N=25)

4.89 (SD: 0.95)

4.74 (SD:0.86) (N=25)

Vazirinejad (2016)58

Psychological training with gradual muscle relaxation


Fatigue (FSS) Favors psychological training with gradual relaxation

42.833 (SD: 8.362)

35.566 (SD:7.609) (N=25)

41.9 (SD: 6.666)

41.1 (SD:5.567) (N=25)


89

Table 9. Fatigue And Quality of Life Data for Evidence Map 2: Complementary and Alternative Medicine (CAM) Interventions Trial Group 1

Specific Treatment


Hedges' g (95% CI)



Group 1 Baseline mean (SD)




Comments

Wade (2002)20

Lofepramine and L-phenylalanine

Placebo 0.36 (0.02 to 0.7)

Fatigue (Chalder Fatigue scale)

Favors Lofepramine and L-phenylalanine

3.9 (SD: 3.4)

1.8 (SD:3.2) (N=67)

3.4 (SD: 3.5)

2.5 (SD:3.2) (N=67)

Torkildsen (2012)50

Omega-3 fatty acids

Placebo NR Fatigue (FSS) Inconclusive NR NR NR NR Only reported that p=0.97

Torkildsen (2012)50

Omega-3 fatty acids

Placebo NR QOL (SF-36 Physical)

Inconclusive NR NR NR NR Only reported that p=0.53


90

Table 10. Fatigue And Quality of Life Data for Evidence Map 2: Other Interventions



Hedges' g (95% CI)






Group 2 Outcome Mean (SD ) (N at Follow-up)

de Carvalho (2012)29

Low frequency magnetic stimulation

Sham stimulation

0.14 (-0.41 to 0.7)


46.5 (SD:16) (N=25)

53.3 (SD: 9.1)

48 (SD:14) (N=25)

de Carvalho (2012)29


Sham stimulation

-0.37 (-0.92 to 0.19)


46 (SD:23) (N=25)

47.2 (SD: 15.6)

45 (SD:16) (N=25)

Piatkowski (2009)32

electromagnetic field therapy

Sham therapy

0.27 (-0.36 to 0.91)


26.84 (SD:12.06) (N=19)

37.83 (SD: 14.26)

36.67 (SD:13.25) (N=18)


91

Table 11. Adverse Effects Data for Evidence Map 2

Trial

Group 1 Specific Treatment

Group 2 Specific Inactive Treatment Adverse Effect

Rate in Group 1

Rate in Group 2

Judgment of AE Severity for This 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 enough to cause study withdrawal

16% (5/31) 9% (3/35) Mild Amantadine: 2 sleep disturbances, 1 palpitations, 2 unspecified. Placebo: 1 headache and 2 unspecified.

Side effects severe enough to cause study withdrawal

6% (2/31) 3% (1/35) Mild Causes of withdrawal from amantadine were rash and anxiety. Cause of withdrawal from placebo was excessive sleep disturbance

Sadeghi-Naini (2017)

Aspirin Placebo Any serious AE 0% (0/51) 0% (0/49) Mild

Study withdrawal after the first visit due to severe depression

4% (2/51) 8% (4/49) Mild

Study withdrawal mid treatment due to GI complaints

4% (2/51) 4% (2/49) Mild

Study withdrawal mid treatment due to other reasons

2% (1/51) 6% (3/49) Mild

Moller (2011) Modafinil Placebo Any serious AE 0% (0/55) 0% (0/55) Moderate

Increased uneasiness/ restlessness

NR NR Moderate Trend of increased rate in 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 led by physical therapist


Any 0% (0/51) 0% (0/48) Mild

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

92

Trial



Rate in Group 1

Rate in Group 2


van den Akker (2017)


Serious AE during followup 9% (3/34) 3% (1/35) Mild Two MS relapses in the CBT group and one surgery. Control group had one MS relapse. Judged to be unrelated to interventions.

Serious AE during treatment period

3% (1/34) 6% (2/35) Mild One MS relapse in the CBT 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 program (CBT, social cognitive, energy effectiveness, self-management)

Usual care Any 0% (0/70) 0% (0/74) Mild

Any 0% (0/70) 0% (0/74) Mild

Dodd (2011) Psychological training with gradual muscle relaxation

No treatment Injury requiring participant to miss a training session

0% (0/37) 0% (0/31) Mild

Muscle stiffness NR NR Mild Table 4 of the author’s report (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 website and video chats

Waitlist Any adverse events 0% (0/23) 0% (0/20) Mild

Turner (2016) Telephone counseling

Self-directed education

Worsening of MS symptoms as measured by the MS-symptom related checklist

NR NR Mild On average participants reported fewer MS symptoms over time, in both groups. No difference between groups, suggesting no AEs of telephone counseling

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

93

Trial



Rate in Group 1

Rate in Group 2


Wade (2002) Lofepramine and L-phenylalanine

Placebo Back pain 3% (2/69) 9% (6/69) Moderate

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 (2012)

Omega-3 fatty acids

Placebo

Abdominal pain 0% (0/46) 7% (3/46) Mild

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 (2012)


Sham stimulation Any 0% (0/25) 0% (0/25) Mild “No side effects were recorded”

AE – Adverse effect MS – Multiple sclerosis NR – Not reported SD – Standard deviation UTI – Urinary tract infection

94

Table 12. Fatigue Data for Evidence Map 3

Trial




Hedges' g (95% CI) (Positive Number Favors Group 1)



Group 1 Outcome Mean (SD) (N at follow-up)


Group 2 Outcome Mean (SD) (N at Follow-up) Comments

van Kessel (2008)64

CBT Relaxation training

Fatigue (Fatigue Scale)

0.52 (0.04 to 1)

Favors CBT 20.94 (SD: 4.25)

10.37 (SD:6.37) (N=34)

20.32 (SD: 4.28)

12.49 (SD:5.24) (N=35)

Mohr (2003)65

Individual CBT Group psychotherapy

Fatigue (Fatigue Assessment Instrument (FAI) total)

0.68 (0.07 to 1.29)

Favors individual CBT

150.1 (SD: 14.21)

140.4 (SD:22.39) (N=22)

151.3 (SD: 15.7)

153.8 (SD:16.58) (N=22)

Mohr (2003)65

Group psychotherapy

Sertraline Fatigue (Fatigue Assessment Instrument (FAI) total)

-0.74 (-1.4 to -0.07)

Favors sertraline

151.3 (SD: 15.7)

153.8 (SD:16.58) (N=22)

152.1 (SD: 22.62)

139 (SD:29.35) (N=16)

Gandolfi (2015)67

Sensory integration balance training

Conventional rehabilitation

Fatigue (FSS) 0.59 (0.11 to 1.07)

Favors sensory integration balance training

4.1 (SD: 1.82)

3.15 (SD:1.6) (N=32)

4.37 (SD: 1.59)

4.4 (SD:1.59) (N=36)

Oken (2004)60


Yoga Fatigue (Multi-dimensional Fatigue Inventory [MFI])

-0.18 (-0.84 to 0.48)


12.1 (SD:2.8) (N=15)

14.7 (SD: 3.3)

13 (SD:2.9) (N=22)

Hasanpour (2016)59

Exercise walking Yoga Fatigue (Rhoten Fatigue Scale)

0.71 (0.07 to 1.35)

Favors exercise

4.9 (SD: 1.333)

2.55 (SD:0.944) (N=20)

4.75 (SD: 1.712)

3.35 (SD:0.812) (N=20)

Romani (2004)63

4'aminopyridine Fluoxetine Fatigue (FSS) 0.21 (-0.44 to 0.86)

Inconclusive 6.8 (SD: NR)

5.5 (SD:NR) (N=18)

6.9 (SD: NR)

5.7 (SD:NR) (N=17)

Tomassini (2004)66

Amantidine L-carnitine Fatigue (FSS) -0.01 (-0.72 to 0.69)

Inconclusive NR NR NR NR Only absolute 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


95

Trial




Hedges' g (95% CI) (Positive Number Favors Group 1)



Group 1 Outcome Mean (SD) (N at follow-up)


Group 2 Outcome Mean (SD) (N at Follow-up) Comments

Straudi (2016)68

Robot-assisted gait training

Conventional walking therapy

Fatigue (FSS) NR Inconclusive NR NR NR NR Only reported that the between group difference was NS

Kalron (2017)69

Pilates PT Fatigue (MFIS) -0.05 (-0.64 to 0.53)


34.7 (SD:19.5) (N=22)

30.4 (SD: 22.3)

28.7 (SD:21.7) (N=23)

Kerling (2015)71

Combined endurance and resistance exercise

Endurance exercise

Fatigue (MFIS) 0.01 (-0.63 to 0.64)


30.6 (SD:16.7) (N=19)

35.1 (SD: 17.4)

30.3 (SD:18.1) (N=18)

Garrett (2013)62


Yoga Fatigue (MFIS) 0.1 (-0.2 to 0.4)

Inconclusive NR (SD: NR)

NR (SD:NR) (N=63)

NR (SD: NR)

NR (SD:NR) (N=63)

We used the reported CIs of individual group change scores to calculate Hedges' g

Aydin (2014)72

Supervised exercise (calisthenic + relaxation)

Exercise (calisthenic + relaxation), home

Fatigue (FSS) -0.1 (-0.75 to 0.54)


4.86 (SD:1.16) (N=16)

4.44 (SD: 1.43)

4.37 (SD:1.43) (N=20)

Razazian (2016)61

Yoga Aquatic exercise

Fatigue (FSS) -0.06 (-0.7 to 0.58)


16.22 (SD:9.6) (N=18)

48.72 (SD: 11.46)

25.28 (SD:11.71) (N=18)

Mohr (2003)65

Individual CBT Sertraline Fatigue (Fatigue Assessment Instrument (FAI) total)

-0.15 (-0.79 to 0.5)


140.4 (SD:22.39) (N=22)

152.1 (SD: 22.62)

139 (SD:29.35) (N=16)

Ehde (2015)70

Telephone delivered self-management

Education with follow-up calls

Fatigue (MFIS) -0.01 (-0.34 to 0.33)


40.2 (SD:16.5) (N=60)

51.2 (SD: 12.7)

43.3 (SD:15.8) (N=80)

Eyssen (2013)73

Client-centered occupational therapy

Standard occupational therapy

Fatigue (MFIS) 0.01 (-0.26 to 0.29)


(SD:NR) (N=107)

48.75 (SD: 13.61)

(SD:NR) (N=100)


96

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.


97

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.

pcori map · fatigue and quality of life data for evidence map 2: exercise interventions ..... 78...

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