Updated PCORI Evidence Map: Treatments for Fatigue in Multiple Sclerosis Prepared by ECRI Institute‐Penn Medicine Evidence‐based Practice Center 5200 Butler Pike Plymouth Meeting, PA 19462 Contributors: Jonathan R. Treadwell, Ph.D., ECRI Institute Amy Tsou, M.D., M.Sc. ECRI Institute Eileen Erinoff, M.S.L.I.S., ECRI Institute Karen Schoelles, M.D., S.M., ECRI Institute Submitted September 2018 i Contents Background ...................................................................................................................................................... 1 Methods ........................................................................................................................................................... 3 Literature Search ....................................................................................................................................... 3 Inclusion Criteria ........................................................................................................................................ 3 Risk of Bias Assessment ............................................................................................................................. 3 Data Extraction and Meta‐Analysis ........................................................................................................... 4 Instruments for Measuring Fatigue ........................................................................................................... 4 Minimum Important Difference (MID) ...................................................................................................... 5 Strength of Evidence Ratings ..................................................................................................................... 5 Map Construction ...................................................................................................................................... 6 Results .............................................................................................................................................................. 6 Evidence Base ............................................................................................................................................ 6 Summary of the Abstracts in Evidence Map 1 (all study designs) ............................................................. 9 Summary of the Trials in Evidence Map 2 (active vs. inactive treatments) ............................................ 13 Summary of the Trials in Evidence Map 3 (active vs. active treatments) ............................................... 18 Limitations ..................................................................................................................................................... 21 Future Research ............................................................................................................................................. 23 References ..................................................................................................................................................... 25 Appendices ..................................................................................................................................................... 47 Appendix A. Literature Search Methods ................................................................................................. 47 Appendix B. Included and Excluded Interventions .................................................................................. 52 Appendix C. Related PCORI‐funded Projects and clinicaltrials.gov records ............................................ 54 Appendix D. Evidence Tables ................................................................................................................... 64 Appendix E. September 2018 Map Updates ........................................................................................... 96 Figures Figure 1. Article Flow ...................................................................................................................................... 8 Figure 2. Screenshot for Evidence Map 1 (overview) ................................................................................... 12 Figure 3. Screenshot for the Exercise section of Evidence Map 2 (comparisons to inactive treatment) .... 15 Figure 4. Screenshot for Evidence Map 3 (comparisons between active treatments) ................................ 20 i 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 ii 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,