Original Research Paper Multiple Sclerosis Journal— Effectiveness of delayed-release dimethyl fumarate Experimental, Translational and Clinical on patient-reported outcomes and clinical October–December 2019, 1–11 DOI: 10.1177/ measures in patients with relapsing–remitting 2055217319887191 ! The Author(s), 2019. multiple sclerosis in a real-world clinical setting: Article reuse guidelines: sagepub.com/journals- permissions PROTEC T Berger , B Brochet, L Brambilla, PS Giacomini , X Montalbán, A Vasco Salgado, R Su and A Bretagne Abstract Background: Patient-reported outcomes (PRO) and clinical outcomes give a broad assessment of relapsing–remitting multiple sclerosis (RRMS) disease. Objective: The aim is to evaluate the effectiveness of delayed-release dimethyl fumarate (DMF) on disease activity and PROs in patients with RRMS in the clinic. Methods: PROTEC, a phase 4, open-label, 12-month observational study, assessed annualized relapse rate (ARR), proportion of patients relapsed, and changes in PROs. Newly diagnosed and early MS (3.5 EDSS and 1 relapse in the prior year) patient subgroups were evaluated. Results: Unadjusted ARR at 12 months post-DMF versus 12 months before DMF initiation was 75% lower (0.161 vs. 0.643, p < 0.0001) overall (n ¼ 1105) and 84%, 77%, and 71% lower in newly diagnosed, 3.5 EDSS, and 1 relapse subgroups, respectively. Overall, 88% of patients were relapse-free 12 months after DMF initiation (84%, newly diagnosed; 88%, 3.5 EDSS; 88%, 1 relapse). PRO measures for fatigue, treatment satisfaction, daily living, and work improved significantly over 12 months of DMF versus baseline. Conclusion: At 12 months after versus 12 months before DMF initiation, ARR was significantly lower, the majority of patients were relapse-free, and multiple PRO measures showed improvement (overall and for subgroups), suggesting that DMF is effective based on clinical outcomes and from a patient perspective. Clinical trial: A Study Evaluating the Effectiveness of Tecfidera (Dimethyl Fumarate) on Multiple Sclerosis (MS) Disease Activity and Patient-Reported Outcomes (PROTEC), NCT01930708, https:// clinicaltrials.gov/ct2/show/NCT01930708. Keywords: Dimethyl fumarate, multiple sclerosis, relapsing–remitting, patient-reported outcome meas- ures, quality of life, treatment outcomes, activities of daily living Date received: 26 April 2019; revised: 11 September 2019; accepted: 19 September 2019 Introduction Correspondence to: and the effects of treatments from the patients’ per- The debilitating character of multiple sclerosis (MS) A Bretagne, makes the assessment of quality of life (QoL) and spective, allowing direct feedback on their well- Biogen, 225 Binney Street, Cambridge, MA, USA. patient-reported outcomes (PROs) very important to being and the impact of treatment on their health. Email: adrien.bretagne@biogen. the patient, their families, and healthcare providers. PROs can provide a broader overall assessment of com PROs are valuable tools for assessing disease states MS disease state and progression than clinical and Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Multiple Sclerosis Journal—Experimental, Translational and Clinical T Berger, neurological outcome measures such as annualized clinic visits scheduled at Baseline, 3, 6, and 12 Universit€atsklinik für Neurologie, Medizinische relapse rate (ARR).1,2 months after DMF treatment initiation. The EDSS Universit€at, Austria scores13 ranged from 0.0 (normal) to 10.0 (death B Brochet, Delayed-release dimethyl fumarate (DMF) is due to MS). Patients were assessed for relapses Groupe Hospitalier Pellegrin Hôpital Pellegrin, France approved as an oral treatment for relapsing and over the 12 months prior to DMF initiation. L Brambilla, relapsing–remitting MS (RRMS).3–5 As of 30 June IRCCS Foundation 2019, >415,000 patients have been treated with Patients Neurological Institute Carlo Besta, Italy DMF, representing >780,000 patient-years of expo- Patient eligibility criteria included: age 18 years, PS Giacomini, sure; 6335 patients (14,065 patient-years) were diagnosis of RRMS, and no prior treatment with Montreal Neurological from clinical trials (Biogen data on file). DMF dem- DMF or second-line MS therapies (e.g. natalizumab, Institute & Hospital, McGill University Health Center, onstrated sustained efficacy on clinical and neurora- fingolimod, alemtuzumab). Exclusion criteria Canada diological measures, and a favorable benefit-risk included pregnancy or risk of pregnancy (unless X Montalbán, profile, in patients with RRMS in two phase 3 stud- approved by Investigator), currently receiving other Division of Neurology, St Michael’s Hospital, ies, DEFINE (NCT00420212) and CONFIRM RRMS therapies (e.g. interferon-b, glatiramer ace- University of Toronto, (NCT00451451), and a phase 4 long-term extension tate, or teriflunomide), hypersensitivity to DMF Canada Department of Neurology- study ENDORSE (NCT00835770).6–8 PROs were active component, or current enrollment in other Neuroimmunology, Centre significantly improved with DMF treatment versus clinical trials, other than Pregnancy Exposure d’Esclerosi Multiple de Catalunya (Cemcat), placebo between integrated analysis of DEFINE and Registry or other non-conflicting studies. Patients Hospital Universitario Vall CONFIRM, measured by EuroQol 5-Dimensions discontinued DMF if their lymphocyte counts were d’Hebron, Spain visual analogue scale (EQ-5D VAS) and 36-Item < 0.5  109/l for 24 weeks. A Vasco Salgado, Hospital Professor Doutor Short Form Health Survey,9 not measured in a clin- Fernando Fonseca, E.P.E., Primary and secondary endpoints Portugal ical setting. Patients with RRMS receiving DMF The primary endpoint reported ARR 12 months after R Su, experienced increased work productivity and DMF treatment in patients with RRMS. The second- Biogen, USA health-related QoL (HRQoL), measured by the ary endpoints evaluated mean changes in PRO A Bretagne, EuroQol-5D (EQ-5D), versus patients receiving scores from Baseline over 12 months; proportion Biogen International GmbH, Switzerland beta interferons or glatiramer acetate.10 of patients with confirmed 24-week EDSS progres- sion at 12 months after enrollment; ARR over 12 Patients with RRMS have better long-term outcomes months before enrollment and at 12 months after when treated early with therapy controlling disease enrollment; proportion of patients relapsed at 12 activity.11 In post hoc analyses, efficacy in patients months after enrollment; proportion of patients with early MS, including newly diagnosed patients, with relapses associated with intravenous steroid was consistent with the overall study populations.8,12 use; and proportion of patients who report taking the prescribed DMF dose, overall percent adherence, This analysis presents the primary outcome results and reasons for not taking full dose over a 12-month from PROTEC (NCT01930708), a 12-month obser- period. Additional outcomes included association vational study that evaluated DMF’s effectiveness between health care resource utilization and disease on disease activity and PROs in patients with activity with PROs over a 12-month period, and RRMS in a real-world clinical setting. An explorato- association between patient-reported adherence and ry endpoint subgroup analysis evaluated DMF’s PROs over a 12-month period. effectiveness in newly diagnosed and other patients with early MS in PROTEC. Patient-reported outcomes For assessment of DMF impact on PROs, patients Materials and methods completed the following instruments (language translated). The PRIMUS-Activity Limitations ques- Study design tionnaire was not completed in Portugal due to lack PROTEC was a phase 4, open-label, single-arm, of available local translation. The Multiple Sclerosis observational, multicenter study conducted in Impact Scale (MSIS-29) measures the physical (20 Europe and Canada from October 2013 to March items) and psychological (nine items) impact of MS 2016. Patients received the approved dosage of on the patient’s previous 2-week day-to-day life.14,15 DMF orally, 120 mg twice daily during the first The Modified Fatigue Impact Scale 5-Item (MFIS-5) week and 240 mg twice daily thereafter. Relapses, consisted of five items describing how fatigue affect- Expanded Disability Status Scale (EDSS), and ed a person.16 Treatment Satisfaction Questionnaire adverse events (AEs) were evaluated at scheduled for Medication 14-item (TSQM-14) measures the and unscheduled visits. PROs were assessed at patient’s level of satisfaction/dissatisfaction with 2 www.sagepub.com/msjetc Berger et al. medication (14 items);17 only patients with previous estimated based on robust standard errors derived treatment were assessed for TSQM-14. EuroQol5D 5 from an unadjusted Poisson regression model using level version (EQ-5D-5L) included two components: the generalized estimating equation method. The the EQ-5D, a descriptive system of the patient’s proportion of patients relapsed from Baseline to 12 health state profile in five dimensions (mobility, months was estimated using the Kaplan–Meier self-care, usual activities, pain/discomfort, and anx- method based on time-to-first-relapse survival distri- iety/depression), and the EQ-5D VAS, a quantitative bution. If patients did not experience a relapse prior measure in which patients described their health on to DMF discontinuation, they were censored on the that day on a scale from 0 to 100.18 For each patient, last date known to be in the study. Mean and median EQ-5D scores were derived based on value sets for change in PROs from Baseline to 12 months was England.18 Patient-reported Indices for Multiple assessed using a Wilcoxon signed-rank test; only Sclerosis activity limitations (PRIMUS-Activity patients with no missing data were included in the Limitations) assessed the patient’s ability to perform tabulation. The frequency of patients with non- various activities of daily living during the previous missing data at each time point was presented. In week without the use of aids (e.g. cane, walker, or general, if there was < 15% of missing data at wheelchair) or assistance (15 items).19,20 Work any time point, data for that specific endpoint were Productivity and Activity Impairment Multiple imputed and the primary analyses were based on Sclerosis Version (WPAI-MS) assessed employment patients with non-missing data. If there was >15% status and, during the previous 7 days, hours worked missing data at any time point, analysis was based on (if employed), hours of missed work due to MS or a mixed-effects model. other reasons, effect on productivity due to MS while working, and activity impairment attributable The estimated proportion of patients with 24-week to health problems (six items);21 WPAI-MS scores confirmed disability progression was based on the are only reported for patients who were employed at Kaplan–Meier product limit method, up to 52 the time of PRO administration. Beck Depression weeks. Confirmed EDSS disability progression was Inventory-Fast Screen (BDI-Fast Screen) evaluated defined as 1.0 point increase in EDSS from a base- depression in patients with medical illness during the line EDSS 1.0, or 1.5 point increase from a base- prior 2 weeks (seven items).22 line EDSS of 0, or 0.5 point increase from a Early MS subgroups baseline EDSS 6 and confirmed at 6 months (154 Three early MS subgroups were pre-specified in the days) after initial progression. Progression could start statistical analysis plan as an exploratory endpoint: at a scheduled assessment or relapse assessment (a) Newly diagnosed: diagnosed with MS 1 year during the treatment period but could be confirmed before study entry, naive to approved MS therapies; during either the treatment and/or follow-up 24-week (b) EDSS:23 baseline EDSS score 3.5; and (c) period. EDSS assessments during relapse assessments Relapse: 1 relapse in the prior year. were not used for confirmation. Patients were cen- sored at the earliest of the last EDSS assessment Statistical analysis date during the treatment period or the last dose of An MS relapse was defined as new or recurrent neu- DMF if they did not have progression. rological symptoms not associated with fever or infection, lasting 24 hours, accompanied by new Analysis methods for the subgroups are consistent with objective neurological findings upon examination by the primary analysis. For the association between the Investigator, followed by 30 days of stability or change from baseline of the PROs and resource utili- improvement (new or recurrent neurological symp- zation (visit with neurologist: Yes/No) and treatment toms that occurred < 30 days following the onset of adherence (80% vs. < 80%), mixed-model repeat- a protocol-defined relapse were considered part of ed measures method was adjusted for baseline PRO the same relapse). ARR was calculated as the total values, baseline EDSS (3.5 vs. >3.5), visit and visit number of relapses in a period divided by the total by the factor of interest interaction term in the model. patient-years of exposure in that period. The primary All analyses were performed using SASVR v9.2 or analyses for ARR, proportion of relapse, and PROs higher (SAS Institute, Cary, NC, USA). were conducted in the primary analysis population, comprising all eligible subjects, who provided Standard protocol approvals, registrations, and signed informed consent, enrolled, and took 1 patient consents dose of DMF. Ninety-five percent confidence inter- The study was approved by central and local ethics nals (CIs) of unadjusted ARR and rate ratio were committees and conducted in accordance with www.sagepub.com/msjetc 3 Multiple Sclerosis Journal—Experimental, Translational and Clinical International Conference on Harmonization initiation. At 1 year following DMF initiation, Guidelines for Good Clinical Practice and the 21 (1.9%) patients had 24-week confirmed disease Declaration of Helsinki. All patients provided writ- progression prevalence; the cumulative incidence ten informed consent. estimated proportion was 2.2% by Kaplan–Meier analysis. Among patients who experienced a relapse Results requiring IV steroid therapy, 97 (9%) experienced one, 11 (1%) experienced two, and one ( < 0.1%) Patients experienced three relapses. Median (min, max) A total of 1105 (1114 enrolled) patients were includ- EDSS scores showed minor improvements from ed in the primary analysis population (Figure 1). Baseline, 2.0 (0.0, 7.0), to Month 12, 1.5 (0.0, 7.0), Most baseline characteristics were similar to the p ¼ 0.0136. phase 3 pivotal studies;6,7 however, there were nota- PROs ble differences for PROTEC (Table 1) versus the A total of 84% of patients treated with DMF com- combined DEFINE/CONFIRM populations24 for pleted the 12-month follow-up period. Overall, relapses in the year before study enrollment (0.6 patients generally demonstrated improvement vs. 1.3) and percentage of patients with any prior across several PRO measures compared with base- MS medication (77% vs. 48%). Median (min, line (Table 2). For MSIS-29, measuring the physical max) duration of DMF treatment was 12.0 (0.03, and psychological impact of MS of the patient’s day- 16.3) months; the majority of patients (941/1106, to-day life, there was significant improvement in 85%) remained on DMF treatment for >9 months. mean (SD) scores between Baseline and Month 12 Mean (SD) overall adherence (weeks with full pre- for physical: 22.8 (21.5) versus 18.3 (19.8), and psy- scribed dose taken divided by the total 0 weeks chological: 34.8 (23.7) versus 25.6 (22.2), during follow-up) was 80 (21%); 16% of patients p < 0.0001 for both comparisons. For MFIS-5, did not take the full prescribed dose during the study assessing the effects of fatigue on physical, cogni- due to side effects. tive, and psychosocial functioning, there was signif- icant improvement in mean (SD) scores between ARR Baseline and Month 12, 8.2 (5.0) versus 6.2 (5.1), Unadjusted ARR at 12 months after DMF treatment p < 0.0001. Similarly, mean (SD) scores between initiation was 75% lower than for 12 months Baseline and Month 12 scores in several WPAI before DMF initiation (0.161 vs. 0.643, p < 0.0001; measures improved, measuring impairment in work Figure 2); and 88% of patients were relapse-free and activities due to MS: overall work impairment in 12 months after DMF initiation versus 48% at the past 7 days, 23.7 (27.1) versus 19.1 (24.7), 12 months before DMF initiation. A total of 710 p ¼ 0.0081; activity impairment in the past 7 days, relapses were experienced in 579 patients in the 28.5 (27.8) versus 22.8 (26.0), p < 0.0001. 12 months prior to initiating DMF, versus 155 relap- ses in 135 patients in the 12 months after treatment Other PRO measures showed small but significant with DMF. Based on Kaplan–Meier estimates, 88% functional differences in scores. TSQM-14 scores of patients were relapse-free 12 months after DMF (patient satisfaction with their current medication) 1114 patients enrolled 1106 patients received ≥1 dose of DMF (safety population) 1105 patients eligible, received ≥1 dose of DMF (analysis population) 1 (<0.1%) patient was not eligible 181 (16.4%) patients withdrew 925 (83.6%) patients Reasons for withdrawal: completed study AEs: 129 (11.7%) Consent withdrawn: 18 (1.6%) Lost to follow-up: 8 (0.7%) Investigator decision: 7 (0.6%) Other: 19 (1.7%) Figure 1. Patient disposition for the PROTEC study is shown. AE: adverse events, DMF: delayed-release DMF. 4 www.sagepub.com/msjetc Berger et al. Table 1. Patient baseline characteristics. Newly Total diagnosed EDSS 3.5 Relapse 1 Characteristic N ¼ 1105 n ¼ 184 n ¼ 978 n ¼ 993 Mean (SD) age, y 38.8 10.0 35 (10) 38 (10) 39 (10) Age category, y, n (%) 18–19 17 (2) 6 (3) 16 (2) 14 (1) 20–29 202 (18) 63 (34) 199 (20) 164 (17) 30–39 367 (33) 60 (33) 338 (35) 329 (33) 40–49 363 (33) 39 (21) 311 (32) 338 (34) 50–59 124 (11) 13 (7) 93 (10) 118 (12) 60 32 (3) 3 (2) 21 (2) 30 (3) Female, n (%) 805 (72) 116 (63) 704 (72) 718 (72) Relapses in year before study enrolment, mean (SD) 0.6 (0. 7) 1.1 (0.7) 0.6 (0.7) 0.5 (0.5) Time since most recent pre-study relapse, mean (SD), ya 4.7 (3.3) 4.1 (3.0) 4.8 (3.3) 5.1 (3.4) Time since diagnosis of MS, mean (SD), y 6.6 (6.1) 0.4 (0.5) 6.0 (5.5) 6.9 (6.1) EDSS score, median (range) 2.0 (0, 7.0) 1.6 (0, 6.5) 1.6 (0, 3.5) 2.0 (0.7) Patients with any prior MS disease-modifying therapy 828 (75) 2 (1) 722 (74) 763 (77) n (%)b,c Interferon beta-1a 499 (45) 0 (0) 442 (46) 460 (45) Glatiramer acetate 318 (28) 0 (0) 276 (29) 293 (29) Interferon beta-1b 175 (16) 0 (0) 139 (15) 157 (15) Median (min, max) time since last MS disease- 0.57 (0.03, 363.2) modifying therapy discontinuation, mo Reason for prior MS treatment discontinuation, n (%)d Tolerability 556 (50) 0 (0) 495 (52) 519 (51) Efficacy reasons 335 (30) 0 (0) 266 (28) 291 (29) Safety 58 (5) 1 (50) 50 (5) 53 (5) Other 167 (15) 1 (50) 145 (15) 156 (15) Total are patients in the primary analysis population. EDSS: Expanded Disability Status Scale; values represent mean (SD) unless stated otherwise. Race was not reported in 1001 patients due to confidentiality reasons implemented during the study. a Based on data from 583 patients. b Only MS therapies taken before the first dose date of DMF initiation were included; patients may have received >1 therapy for MS. c Medications previously taken by >10% of patients are shown. Other medications taken by >1% of patients include azathioprine, interferon beta, interferon, and teriflunomide. d If patients have >1 discontinuation reason for same MS therapy, only the last reason was used. improved significantly between Baseline and 3.1 (4.6) at Baseline versus 2.6 (4.3) at Month 12, Month 12 for the global score and its components: suggesting no significant change in patients’ ability TSQM-14 global score, 51.4 (22.5) versus 73.6 to perform various activities of daily living without (21.0); effectiveness, 54.3 (21.7) versus 70.1 aids or assistance. There was no evidence of change (24.7); side effects, 60.1 (30.6) versus 85.4 (19.4); in PRO scores between Baseline and Month 12 for convenience, 52.4 (21.2) versus 85.5 (17.2), patients who visited a neurologist and those who did p < 0.0001 for all comparisons. There were signifi- not. Similarly, there was no evidence of a change in cant improvements from Baseline to Month 12 for PRO scores between Baseline and Month 12 patients EQ-5D, 0.8 (0.2) versus 0.9 (0.2); EQ-5D VAS, 74.1 with < 80% adherence versus 80% adherence. (18.7) versus 79 (17.5); and BDI-FAST, assessing depressive symptoms, 2.8 (3.2) versus 1.9 (3.0), Early MS and other subgroups: Relapses and PRO p < 0.0001 for all comparisons. The effectiveness of DMF in newly diagnosed patients and different levels of disability was PRIMUS-Activity Limitations scores remained analyzed by dividing the population into stable between Baseline and Month 12, mean (SD) subgroups. Among the patients who received 1 www.sagepub.com/msjetc 5 Multiple Sclerosis Journal—Experimental, Translational and Clinical (a) Rate ratio (95% CI)a 0.25 (0.21–0.30) 0.8 0.64 p < 0.0001 (0.60–0.69) Unadjusted ARRb (95% CI)a 0.6 75% lower 0.4 0.16 (0.14–0.19) 0.2 0.0 12 months 12 months before DMF initiation after DMF initiation (b) Rate ratio (95% CI) 1.8 12 months before DMF initiation 0.16 (0.11–0.23) 12 months after DMF initiation 1.6 Unadjusted ARR (95% CI) 1.4 1.13 (1.04–1.23) Rate ratio (95% CI) 1.2 84% 0.23 (0.19–0.28) Rate ratio (95% CI) lower 1.0 0.29 (0.24–0.35) 77% 0.64 0.8 lower 71% (0.59–0.68) 0.47 lower 0.6 (0.44–0.50) 0.18 0.4 (0.13–0.26) 0.15 0.14 (0.12–0.18) (0.11–0.17) 0.2 0.0 Newly diagnosed ≤3.5 EDSS ≤1 Relapse (n = 184) (n = 978) (n = 993) Figure 2. ARR at 12 months before and after DMF initiation for (A) all patients and (B) early MS subgroups. a Based on empirical (robust) SE from a generalized estimating equation using an unadjusted Poisson regression model. b ARR was calculated as the total number of relapses that occurred during that period of time for all patients, divided by the total number of patient-years followed in that period. Subgroups are defined as: EDSS ¼ baseline EDSS score 3.5; Relapse ¼ 1 relapse in the prior year. DMF: delayed-release DMF. dose of DMF, 184 were newly diagnosed, 978 in the subgroups for MSIS-29, MFIS-5, EQ-5D, and EQ- EDSS 3.5 subgroup, and 993 in the 1 relapse 5D VAS (Table 3). subgroup. Similar to the overall population, ARR at 12 months after DMF initiation was 84% lower Safety than ARR estimated for the 12 months before DMF Overall, 914 (83%) patients experienced an initiation in newly diagnosed patients, 77% in the AE; serious AEs occurred in 41 (4%) patients EDSS 3.5 subgroup, and 71% in the 1 relapse (Table 4). One death occurred due to an accident, subgroups, p < 0.0001 for all subgroup (Figure 2(b)). deemed unrelated to DMF treatment. A total of 126 Based on Kaplan–Meier estimates, the percentages (11%) patients discontinued DMF treatment due to of patients relapse-free 12 months after DMF initia- AEs. The most common treatment-related AEs lead- tion were 84.2% for newly diagnosed patients, ing to DMF discontinuation (1% of patients) 87.7% in the EDSS 3.5 subgroup, and 88.4% in were abdominal pain (2%), diarrhea (1%), and vom- the 1 relapse subgroup. iting (2%). Significant improvements in scores from baseline to No cases of progressive multifocal leukoencephalop- 12 months were observed across all early MS athy were reported. Mean absolute lymphocyte counts at 12 months (1.26  109/l) remained above 6 www.sagepub.com/msjetc Berger et al. Table 2. Mean change in PROs from baseline to 12 months. Mean (SD) change from baseline to Month 12 Measure Description Component Improved Stable Worsened p-value MSIS-29a 20 items assess physical impact Physical impact þ <0.0001 of MS in terms of mobility n ¼ 868 –3.0 (14.1) and self-care 9 items assess psychological Psychological þ <0.0001 impact of MS impact –8.0 (18.6) n ¼ 860 MFIS-5b 5 items assess how fatigue n ¼ 867 þ <0.0001 impacts patients’ lives –1.7 (3.8) TSQM-14c 14 items assess patient treatment Effectiveness þ <0.0001 satisfaction n ¼ 492 14.4 (29.5) Side effects þ <0.0001 n ¼ 500 25.4 (31.4) Convenience þ <0.0001 n ¼ 505 33.4 (25.7) Global score þ <0.0001 n ¼ 511 21.8 (26.9) EQ-5D-5Ld 5 items assess mobility, self- EQ-5D þ <0.0001 care, usual activities, pain and n ¼ 792 0.02 (0.1) discomfort, anxiety and EQ-5D VAS þ <0.0001 depression n ¼ 803 3.7 (15.9) PRIMUS 15 items assess activities of n ¼ 545  0.2134 activity daily living –0.14 (3.2) limitationse WPAI-MSf 6 items assess the number of Work impairmentf þ 0.008 work hours missed, impact on n ¼ 327 –2.2 (19.5) productivity, and daily activi- Activity impairment þ <0.0001 ties during past 7 days n ¼ 851 –4.2 (22.3) BDI-Fast 7 items assess depression during n ¼ 854 þ <0.0001 Screeng the past 2 weeks –0.8 (2.5) EDSSh Assesses disease progression n ¼ 940  0.0136 –0.05 (0.65) BDI-Fast Screen: Beck Depression Inventory-Fast Screen; EDSS: Expanded Disability Status Scale; EQ-5D-5L: EuroQol-5D 5-level version; MFIS-5: Modified Fatigue Impact Scale 5-item version; MSIS-29, Multiple Sclerosis Impact Scale; PRIMUS: Patient-Reported Indices for Multiple Sclerosis; PRO: patient-reported outcome; TSQM-14: Treatment Satisfaction Questionnaire for Medication; WPAI-MS: Work Productivity and Activity Impairment for Multiple Sclerosis. Mean change in PROs from baseline to 12 months was assessed using a Wilcoxon signed-rank test. a Lower score indicates better outcome; range, 0–100 (scores were transformed). b Lower score indicates improved functioning; range, 0–20. c Higher score indicates greater satisfaction; range, 0–100; only patients with previous treatment were assessed. d Higher score indicates better health; range, 0–100. e Higher score indicates better outcome; range, 0–30. f Higher score indicates higher impairment and lower productivity; scores are only reported for patients who were employed at the time of PRO administration. g Lower score indicates less severe depressive symptoms; range, 0–21. h Lower score indicates less severe disability symptoms; range, 0–10. www.sagepub.com/msjetc 7 Multiple Sclerosis Journal—Experimental, Translational and Clinical Table 3. Change in PROs from baseline to 12 months in early MS subgroups. Newly diagnosed EDSS 3.5 Relapse 1 Measure Description Component (n ¼ 184) (n ¼ 978) (n ¼ 993) MSIS-29a 20 items assess physical Physical þ þ þ impact of MS in terms impact –3.1 (14.8) –2.7 (13.4) –3.2 (14.2) of mobility and self-care 9 items assess psycholog- Psychological þ þ þ ical impact of MS impact –9.1 (16.9) –8.0 (18.2) –8.1 (18.5) MFIS-5b 5 items assess how fatigue þ þ þ impacts patients’ lives –1.6 (3.5) –1.7 (3.7) –1.7 (3.8) EQ-5D VASc 5 items assess mobility, þ þ þ self-care, usual activi- 4.1 (13.7) 3.6 (15.1) 3.7 (15.9) ties, pain and discom- fort, anxiety and depression EDSS: Expanded Disability Status Scale; EQ-5D VAS: EQ-5D visual analogue scale; MFIS-5: Modified Fatigue Impact Scale 5-item version; MSIS-29: Multiple Sclerosis Impact Scale; PRO: patient-reported outcome. þ ¼ Statistically significant improvement;  ¼ no statistically significant change; – ¼ statistically significant worsening. a Lower score indicates better outcome; range, 0–100 (scores were transformed). b Lower score indicates improved functioning; range, 0–20. c Higher score indicates better health; range, 0–100. Table 4. Summary of adverse events. Discussion The results reported are consistent with DMF effec- Total tiveness data from other real-world phase 4 studies AE, n (%) n ¼ 1106 (RESPOND; NCT01903291),25 supporting the find- Any AE 914 (83) ings from phase 3 studies of DMF.6,7 Unadjusted Most common AEs in 10% patients ARR at 12 months after DMF treatment initiation Flushing 477 (43) was significantly lower compared with 12 months Diarrhea 172 (16) before DMF initiation. The majority of patients Abdominal pain upper 120 (11) were relapse-free 12 months after DMF initiation. Abdominal pain 115 (10) Safety and tolerability were consistent with the Any SAE 41 (4) known safety profile of DMF.3,4,6,7,24 Lymphocyte Most frequently occurring SAEs in 2 patients counts were similar to those reported in pivotal clin- Fall 4 (<1) ical trials and clinical practice.6,7,26–28 Statistically Lymphopenia 3 (<1) significant improvements from baseline to 12 Breast cancer 2 (<1) months were observed for the majority of PROs, MS relapse 2 (<1) indicating that DMF is an effective MS treatment from a patient perspective as well as based on clas- AE: adverse event; SAE: serious adverse event. sical clinical outcomes. Clinical significance of PROs scores the lower limit of normal (0.91  109/l) (Table 5), In patients with MS and other chronic diseases, a consistent with trial data.6,7 Of the 400 patients with widely used threshold for discrimination of mean- 2 post-baseline lymphocyte assessments, 44 (11%) ingful change in HRQoL is 1/2 SD change in PRO had moderate, persistent lymphopenia (2 consecu- score over 1 year.29 In a population of patients with tive lymphocyte levels of < 0.8  109/l 180 days RRMS, a 7.50 point worsening was determined to apart), and four (1%) had severe, persistent lympho- be a practical threshold for identifying a clinically penia (two consecutive lymphocyte levels of significant change in the physical impact of MS < 0.5  109/l 180 days apart). using the MSIS-29 physical score.30 The threshold 8 www.sagepub.com/msjetc Berger et al. Table 5. Lower lymphocyte counts. Total Mean (SD) lymphocyte counts,  109/l 1.26 (0.55) Baseline, n ¼ 1038 1.93 (0.61) Month 12, n ¼ 897 1.26 (0.55) 0.8 – <0.91 (LLN), n/N (%)a 69/831 (8) 0.5 – <0.8, n/N (%)a 133/831 (16) <0.5, n/N (%)a 17/831 (2) Patients with 2 post-baseline lymphocyte assessments, n 400 Moderate, persistent lymphopeniab, n 44 Severe, persistent lymphopeniac, n 4 ALC: absolute lymphocyte count; LLN: lower limit of normal. a For patients with at least 1 baseline assessment >LLN. b ALC of at least 2 consecutive lymphocyte levels of <0.8  109/L 180 days apart. c ALC of at least 2 consecutive lymphocyte levels of <0.5  109/L 180 days apart. for worsening was defined as < –0.074 points for therapies (DMTs) for MS. Therefore, familiarity to EQ-5D31 and < –5.5 points for EQ-5D VAS,32 compliance with treatment and dosage requirements although these thresholds were not calculated in impact the generalizability of results for treatment- patients with MS. In this analysis, the mean naı̈ve or less adherent patients. Due to the real-world change was –3.0 for MSIS-29 physical score, 0.02 nature of the study, eligibility criteria did not restrict for EQ-5D, and 3.7 for EQ-5D VAS: statistically participation to patients with 1 relapse over the significant, although they may not be meaningful 12-month period prior to study entry, as in clinical changes based on criteria described in pre- DEFINE and CONFIRM, rendering it possible that vious studies. By the 1/2 SD rule, MFIS-5 (mean patients in this study had a less severe progression of –1.7; SD 3.8), TSQM-14 side effects, TSQM-14 MS at enrollment. Therefore, these patients may convenience, and TSQM-14 global score reached have exhibited lower risk possibly resulting in clinically significant change. lower incidence of relapse over the study period, regardless of treatment. The study design may Early MS treatment has been associated with a impede researchers dictating when PRO assessments reduction in disease progression.33,34 When consid- are completed relative to relapses. PRO assessments ering the optimal treatment for reducing disease pro- obtained shortly after relapse have a greater risk of gression risk in patients with early MS, relapses, being affected by the relapse compared with PROs MRI lesions, disability progression, and brain obtained with no recent relapse, although compari- volume loss are four key measures of disease activ- sons of PRO outcomes in patients with or without ity.35 For treatment-naı̈ve patients, IFN-b, glatiramer relapses during the study found either a marginal acetate, teriflunomide, and DMF, followed by fingo- difference or no difference in the change from limod, natalizumab, and alemtuzumab, have been Baseline to Month 12. Missing data from patient- suggested in patients with breakthrough disease reported measures is a limitation of real-world stud- activity.35 ARR and PRO results for the newly diag- ies; however, mitigating the risk of missing data nosed subgroup and the subgroups with EDSS 3.5 impacting study results, the proportion of missing or relapse 1 in the prior year were similar to the data was described and accounted for throughout overall group, indicating DMF is effective in a broad the statistical analyses. Unfortunately, the influence range of patients. of patients “not missing at random” may introduce bias in both the estimate and variance for which the The results and interpretations are subject to several sensitivity analysis cannot account. To minimize limitations common to real-world studies, including potential bias due to methods of data collection, the observational nature of the study, short duration case report forms were carefully designed, with of follow-up time on DMF, and lack of active com- clear instructions and training provided to site parators. Potential bias arises due to regression to staff; furthermore, mitigations were carried out if the mean because the majority of patients enrolled data entry concerns were identified. Finally, the had previous experience with disease-modifying 11.7% of patients who discontinued due to AEs www.sagepub.com/msjetc 9 Multiple Sclerosis Journal—Experimental, Translational and Clinical may introduce possible confounding or bias in the Hôpital Pellegrin) has received support for clinical trials QoL measures, given the symptomatic nature of and research activities from Actelion, Bayer HealthCare, some AEs and their impact of QoL outcomes. Biogen, Genzyme, Merck Serono, MedDay, Novartis, Roche, and Teva; LB: received honoraria for speaking Comparing treatment-satisfaction scores between pre- from Novartis and for traveling from Sanofi-Genzyme and viously discontinued drugs with treatment-satisfaction Roche; she acted as an Advisory Board member of Sanofi- scores in drugs not discontinued for 12 months Genzyme and principal investigator in clinical trials for Roche; sub-investigator in clinical trial for Novartis, could be biased in favor of DMF purely because of Biogen, Sanofi-Genzyme, Merck; XM: received speaking patient selection. Sensitivity analyses were performed honoraria and travel expenses for participation in scientific for primary and secondary endpoints using patient meetings, has been a steering committee member of clinical populations who completed the full study period trials or participated in advisory boards of clinical trials in (completer population), in order to evaluate potential the past years with Actelion, Bayer, Biogen, Celgene, effects of early study withdrawal on analytic results. Excemed, Genzyme, Merck, MSIF, NMSS, Novartis, Results were similar between the completer and anal- Roche, Sanofi-Genzyme, and Teva Pharmaceutical; PSG: ysis populations. Also, since the exclusions criteria consulting/speaker fees from/advisory boards for Actelion, were only based on last DMT, the assessment may Allergan, Bayer, Biogen, EMD Serono, Merz, Novartis, be limited if patients were on multiple DMTs and Pendopharm, Roche, Sanofi-Genzyme, and Teva omitting the type or strength of DMT. Neuroscience; research support from Biogen; consultant for NeuroRx Research; principal investigator/sub- investigator for clinical trials for Actelion, Alexion, Bayer Conclusions HealthCare, Biogen, Elan, EMD Serono, GlaxoSmithKline, Overall, the results suggest that DMF may offer an MedImmune, Novartis, Ono, Roche-Genentech, Sanofi- effective treatment option for patients with RRMS, Aventis, and Teva Neuroscience; AVS: consultant for both from a clinical perspective and based on Biogen, Merck Serono, Novartis, and Sanofi-Genentech; patients’ satisfaction with DMF treatment in relation fees from Roche and Boehringer Ingelheim; RS and AB: to their personal quality of life, health status, and employees of and hold stock/stock options in Biogen physical abilities. Funding Acknowledgements This study was supported by Biogen. Biogen provided funding for medical writing support in the development of this paper; Ana Antaloae, PhD and ORCID iDs Karen Spach, PhD from Excel Scientific Solutions wrote the first draft of the manuscript based on input from T Berger https://orcid.org/0000-0001-5626-1144 authors, and Elizabeth Wassmer from Excel Scientific PS Giacomini https://orcid.org/0000-0002-1346-3042 Solutions copyedited and styled the manuscript per journal requirements. Biogen reviewed and provided feedback on the paper. The authors had full editorial control of the References paper, and provided their final approval of all content. 1. Nortvedt MW and Riise T. The use of quality of life measures in multiple sclerosis research. Mult Scler Data availability 2003; 9(1): 63–72. The datasets used and/or analyzed during the current study 2. Deshpande PR, Rajan S and Sudeepthi BL, Abdul are available from the corresponding author upon reason- Nazir CP. Patient-reported outcomes: A new era able request. 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