i 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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PCORI Map · 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
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Updated PCORI Evidence Map:
Treatments for Fatigue in
Multiple Sclerosis
Prepared by
ECRI Institute‐Penn Medicine Evidence‐based Practice Center
Literature Search ....................................................................................................................................... 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
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
Future Research ............................................................................................................................................. 23
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
g=0.72 (based on 3 RCTs27,60,62) Strength: Moderate
0.94 points 11 points
g=0.3 (based on 3 RCTs27,60,62) Strength: Moderate
Behavioral/Education: Relaxation training
g=0.67 (based on 2 RCTs57,58) Strength: Low
0.87 points 10 points Inconclusive
Behavioral/Education: Education on physical activity
g=0.59 (based on 3 RCTs28,48,56) Strength: Moderate
0.77 points 9 points Inconclusive
Behavioral/Education: Fatigue: Applying Cognitive behavioural and Energy effectiveness Techniques to lifeStyle (FACETS) program
g=0.43 (based on 1 RCT49) Strength: Moderate
0.56 points 6 points Inconclusive
CAM: Lofepramine and L-phenylalanine
g=0.36 (based on 1 RCT20) Strength: Moderate
0.47 points 5 points Inconclusive
Behavioral/Education: Fatigue management program
g=0.33 (based on 5 RCTs23,30,34,35,37) Strength: Moderate
0.43 points 5 points
g=0.26 (based on 3 RCTs30,34,37) Strength: Moderate
FSS – Fatigue Severity Scale, which ranges from 1–7 where higher numbers represent greater fatigue. Learmonth et al. (2013)14 estimated that the MID is 1.9 points, whereas Robinson et al. (2009)15 estimated it at 1 point. g – Hedges’ g, which is a standardized effect size. Hedges’ g is an N‐corrected form of the standardized mean difference (SMD), which itself is the difference between groups divided by the pooled standard deviation. MFIS – Modified Fatigue Impact Scale, which ranges from 0–84 where higher numbers represent greater fatigue. Learmonth et al. (2013)14 estimated that the MID is 20.2 points. RCTs — Randomized controlled trials
Summary of the Trials in Evidence Map 3 (active vs. active treatments)
We included 15 randomized trials for Evidence Map 3 (see Table 12 in Appendix D). In this map (see
a screenshot in Figure 4 below), dark red bubbles indicate one treatment had a greater impact on
fatigue compared to the other (hovering over the bubble displays which intervention was favored).
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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.
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Figure 4. Screenshot for Evidence Map 3 (comparisons between active treatments)
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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
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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.
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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.
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The use of evidence maps to distill the results of a comprehensive literature search and data synthesis
into an interactive Web‐based format may be a significant step forward. Important next steps should
include pilot testing with qualitative feedback to identify potential improvements for usability and
prioritizing content.
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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
Concept Search Statement # Identified
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
Concept Search Statement # Identified
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
Concept Search Statement # Identified
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
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
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
Concept Search Statement # Identified
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
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
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)
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
NCT Number Title Start Date and Projected End Date
Study Design
Number of Patients
Intervention(s) Outcomes
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
Table 4. Related Records in clinicaltrials.gov, continued
57
NCT Number Title Start Date and Projected End Date
Study Design
Number of Patients
Intervention(s) Outcomes
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
Table 4. Related Records in clinicaltrials.gov, continued
58
NCT Number Title Start Date and Projected End Date
Study Design
Number of Patients
Intervention(s) Outcomes
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
Table 4. Related Records in clinicaltrials.gov, continued
59
NCT Number Title Start Date and Projected End Date
Study Design
Number of Patients
Intervention(s) Outcomes
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
RCT 88 Supervised aerobic exercise
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
Table 4. Related Records in clinicaltrials.gov, continued
60
NCT Number Title Start Date and Projected End Date
Study Design
Number of Patients
Intervention(s) Outcomes
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
RCT 96 Supervised aerobic exercise
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)
Table 4. Related Records in clinicaltrials.gov, continued
61
NCT Number Title Start Date and Projected End Date
Study Design
Number of Patients
Intervention(s) Outcomes
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.
Table 4. Related Records in clinicaltrials.gov, continued
62
NCT Number Title Start Date and Projected End Date
Study Design
Number of Patients
Intervention(s) Outcomes
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
RCT 40 Supervised aerobic exercise
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
Table 4. Related Records in clinicaltrials.gov, continued
63
NCT Number Title Start Date and Projected End Date
Study Design
Number of Patients
Intervention(s) Outcomes
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
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
RCT 10 Supervised aerobic exercise
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
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
Table 5. Data for Evidence Map 1 (Abstracts on Interventions for Fatigue in MS), contnued
76
Reference Intervention Category
Type of Intervention Specific Intervention Total Patients in Study
Number Assigned to This Treatment Group
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)
Group 2 Baseline Mean (SD)
Group 2 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)
Inconclusive 40.8 (SD: 13.2)
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
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)
Group 2 Baseline Mean (SD)
Group 2 Outcome Mean (SD) (N at Follow-up)
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
Aquatic therapy Usual care 0.84 (0.18 to 1.5)
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
Aquatic therapy Usual care 1.47 (0.76 to 2.19)
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
FSS- Fatigue Severity Scale MFIS – Modified Fatidue Impact Scale NR – Not reported QOL – Quality of life SD – Standard deviation
83
Table 8. Fatigue and Quality of Life Data for Evidence Map 2: Behavioral/Educational 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)
Group 2 Baseline Mean (SD)
Group 2 Outcome Mean (SD) (N at Follow-up)
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
Behavioral intervention to encourage physical activity via education
Waitlist 0.43 (-0.02 to 0.89)
Fatigue (MFIS total)
Inconclusive (SD: NR)
35.7 (SD:10.9) (N=37)
(SD: NR)
40.5 (SD:11.2) (N=39)
Pilutti (2014)48
Behavioral intervention to encourage physical activity via education
Waitlist 0.44 (-0.01 to 0.9)
QOL (MSIS-29 Physical (higher scores are WORSE))
Inconclusive (SD: NR)
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)
No treatment 2.43 (1.77 to 3.08)
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=)
Table 8. Fatigue and Quality of Life Data for Evidence Map 2: Behavioral/Educational Interventions
84
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)
Group 2 Baseline Mean (SD)
Group 2 Outcome Mean (SD) (N at Follow-up)
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)
QOL (SF-36 physical functioning)
Inconclusive (SD: NR)
(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)
Inconclusive 44.3 (SD: 7.9)
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])
Inconclusive 49.6 (SD: 19.1)
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])
Inconclusive 79.94 (SD: 30.48)
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)
Table 8. Fatigue and Quality of Life Data for Evidence Map 2: Behavioral/Educational Interventions
85
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)
Group 2 Baseline Mean (SD)
Group 2 Outcome Mean (SD) (N at Follow-up)
Comments
Finlayson (2011)34
Fatigue management program via tele-conference
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)
Fatigue (FSS) Inconclusive 52.47 (SD: 11.3)
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
Education with nurse consultations
0.11 (-0.36 to 0.58)
Fatigue (MFIS total)
Inconclusive 45.1 (SD: 11.7)
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)
Inconclusive 57.18 (SD: 21.56)
60.92 (SD:20.91) (N=34)
58.74 (SD: 19.3)
61.36 (SD:20.07) (N=33)
Finlayson (2011)34
Fatigue management program via tele-conference
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
Table 8. Fatigue and Quality of Life Data for Evidence Map 2: Behavioral/Educational Interventions
86
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)
Group 2 Baseline Mean (SD)
Group 2 Outcome Mean (SD) (N at Follow-up)
Comments
Blikman (2017)37
Individual energy conservation management with occupational therapist
Education with nurse consultations
0.25 (-0.22 to 0.73)
QOL (SF-36 physical function (SF-36 total was not reported))
Inconclusive 53.9 (SD: 24.8)
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)
No treatment 1.27 (0.56 to 1.97)
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)
Inconclusive 42.9 (SD: 8.5)
38.9 (SD:9.7) (N=39)
44.2 (SD: 6)
39.5 (SD:9) (N=35)
van den Akker (2017)38
CBT Nurse consultations
0 (-0.45 to 0.45)
Fatigue (FSS) Inconclusive 5.4 (SD: 0.7)
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)
No treatment 1.11 (0.43 to 1.8)
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)
van den Akker (2017)38
CBT Nurse consultations
-0.31 (-0.76 to 0.14)
Fatigue (MFIS total)
Inconclusive 47.3 (SD: 12.5)
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)
Inconclusive 47.39 (SD: 18.07)
63.32 (SD:17.25) (N=15)
43.28 (SD: 17.63)
49.33 (SD:21.32) (N=15)
van den Akker (2017)38
CBT Nurse consultations
0.09 (-0.36 to 0.54)
QOL (SF-36 physical function (SF-36 total was not reported))
Inconclusive 55.8 (SD: 22.1)
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)
Inconclusive 64.2 (SD: 18.7)
59 (SD:17.7) (N=50)
66.3 (SD: 15.6)
64.4 (SD:16.5) (N=28)
Table 8. Fatigue and Quality of Life Data for Evidence Map 2: Behavioral/Educational Interventions
87
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)
Group 2 Baseline Mean (SD)
Group 2 Outcome Mean (SD) (N at Follow-up)
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)
Fatigue (FSS) Inconclusive 34.73 (SD: 21.97)
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)
Fatigue (MFIS) Inconclusive 36.47 (SD: 13.8)
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)
QOL (MSIS-29 Physical [higher scores are WORSE])
Inconclusive 25 (SD: 16.9)
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)
Inconclusive 60.09 (SD: 11.33)
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)
Fatigue (FSS) Inconclusive 39.91 (SD: 14.45)
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)
Used reported CIs of individual group change scores to calculate Hedges' g
Bogosian (2015)47
Mindfulness (online)
Usual care 0.23 (-0.46 to 0.91)
QOL (Euro QOL [EQ-5D])
Inconclusive 0.41 (SD: 0.39)
0.51 (SD:0.37) (N=14)
0.48 (SD: 0.33)
0.5 (SD:0.29) (N=18)
Table 8. Fatigue and Quality of Life Data for Evidence Map 2: Behavioral/Educational Interventions
88
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)
Group 2 Baseline Mean (SD)
Group 2 Outcome Mean (SD) (N at Follow-up)
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)
Used reported CIs of individual group change scores to calculate Hedges' g
Nazari (2015)57
Relaxation training
Usual care 0.47 (-0.09 to 1.03)
Fatigue (FSS) Inconclusive 4.93 (SD: 0.87)
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
No treatment 0.9 (0.32 to 1.49)
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)
FSS- Fatigue Severity Scale MFIS – Modified Fatidue Impact Scale NR – Not reported QOL – Quality of life SD – Standard deviation
89
Table 9. Fatigue And Quality of Life Data for Evidence Map 2: Complementary and Alternative Medicine (CAM) 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)
Group 2 Baseline Mean (SD)
Group 2 Outcome Mean (SD) (N at Follow-up)
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
FSS- Fatigue Severity Scale MFIS – Modified Fatidue Impact Scale NR – Not reported QOL – Quality of life SD – Standard deviation
90
Table 10. Fatigue And Quality of Life Data for Evidence Map 2: Other 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)
Group 2 Baseline Mean (SD)
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)
Fatigue (FSS) Inconclusive 49.9 (SD: 12.5)
46.5 (SD:16) (N=25)
53.3 (SD: 9.1)
48 (SD:14) (N=25)
de Carvalho (2012)29
Low frequency magnetic stimulation
Sham stimulation
-0.37 (-0.92 to 0.19)
Fatigue (MFIS) Inconclusive 41.6 (SD: 13.6)
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)
Fatigue (MFIS) Inconclusive 31.68 (SD: 13.24)
26.84 (SD:12.06) (N=19)
37.83 (SD: 14.26)
36.67 (SD:13.25) (N=18)
FSS- Fatigue Severity Scale MFIS – Modified Fatidue Impact Scale NR – Not reported QOL – Quality of life SD – Standard deviation
91
Table 11. Adverse Effects Data for Evidence Map 2
Trial
Group 1 Specific Treatment
Group 2 Specific Inactive Treatment Adverse Effect
Tarakci (2013) Group exercise led by physical therapist
Monthly phone call from a neurologist
Any 0% (0/51) 0% (0/48) Mild
Table 11. Adverse Effects Data for Evidence Map 2, continued
92
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
van den Akker (2017)
CBT Nurse consultations
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
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
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)
Low frequency magnetic stimulation
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
Group 1 Specific Treatment
Group 2 Specific Treatment
Outcome (Instrument)
Hedges' g (95% CI) (Positive Number Favors Group 1)
Single Study Finding
Group 1 Baseline Mean (SD)
Group 1 Outcome Mean (SD) (N at follow-up)
Group 2 Baseline Mean (SD)
Group 2 Outcome Mean (SD) (N at Follow-up) Comments
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
Table 12. Fatigue Data for Evidence Map 3
95
Trial
Group 1 Specific Treatment
Group 2 Specific Treatment
Outcome (Instrument)
Hedges' g (95% CI) (Positive Number Favors Group 1)
Single Study Finding
Group 1 Baseline Mean (SD)
Group 1 Outcome Mean (SD) (N at follow-up)
Group 2 Baseline Mean (SD)
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)
Inconclusive 35.3 (SD: 21.6)
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)
Inconclusive 35.5 (SD: 17)
30.6 (SD:16.7) (N=19)
35.1 (SD: 17.4)
30.3 (SD:18.1) (N=18)
Garrett (2013)62
Exercise led by physiotherapist or fitness instructor
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