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Impact of daclizumab versus interferon beta-1a on patient-reported outcomes in relapsing-remitting multiple sclerosis

Multiple Sclerosis and Related Disorders, January 2017, Pages 18 - 24

Abstract

Background

Patient-reported outcomes (PROs) provide information on treatment effects from the patient's perspective that complement outcomes on clinical measures. In DECIDE, daclizumab demonstrated superior efficacy in reducing relapses, 24-week confirmed disability progression, and brain lesions (assessed by magnetic resonance imaging [MRI]) versus intramuscular interferon beta-1a in relapsing-remitting multiple sclerosis.

Objective

To examine the impact of daclizumab versus interferon beta-1a on PROs in DECIDE.

Methods

DECIDE was a randomized, double-blind, active-controlled, phase 3 study comparing daclizumab 150 mg subcutaneous every 4 weeks with interferon beta-1a 30 mcg intramuscular once weekly. The 29-item Multiple Sclerosis Impact Scale (MSIS-29) and EuroQoL 5-Dimensions (EQ-5D) were assessed at baseline and every 24 weeks. Mean changes from baseline were analyzed using analysis of covariance models. Individual items for the MSIS-29 physical (PHYS) and psychological (PSYCH) subscales were analyzed post hoc.

Results

Daclizumab treatment resulted in greater mean improvements relative to baseline in MSIS-29 PHYS and PSYCH scores starting at week 24 that persisted over 96 weeks. Mean improvements from baseline in MSIS-29 PHYS and PSYCH scores were significantly greater for daclizumab versus intramuscular interferon beta-1a at week 96. Daclizumab-treated patients showed steady improvements in EQ-5D health utility index and EQ-5D visual analog scale scores over the study period, with significantly greater improvements versus intramuscular interferon beta-1a at week 96 (p=0.0048 and p=0.0006, respectively).

Conclusions

Improvements in patient-reported physical and psychological functioning and general health status with daclizumab compared with intramuscular interferon beta-1a are consistent with outcomes on clinical and brain MRI lesion measures in DECIDE (NCT01064401).

Highlights

  • Daclizumab demonstrated superior efficacy vs IM interferon beta-1a in DECIDE.
  • DECIDE included PROs to assess impact of treatment from the patient's perspective.
  • MSIS-29 score improvement was significantly greater for daclizumab at week 96.
  • EQ-5D score improvement was significantly greater for daclizumab at week 96.
  • Improvement in PROs with daclizumab was consistent with clinical/MRI outcomes.

Abbreviations: ARR - annualized relapse rate, BDI-II - Beck Depression Inventory-II, EQ-5D - Euro-Qol 5-Dimensions, IFN - interferon, IM - intramuscular, MRI - magnetic resonance imaging, MS - multiple sclerosis, MSIS-29 - 29-item Multiple Sclerosis Impact Scale, OR - odds ratio, PHYS - physical impact subscale, PRO - patient-reported outcome, PSYCH - psychological impact subscale, QoL - quality of life, RRMS - relapsing-remitting multiple sclerosis, SC - subcutaneous, VAS - visual analog scale.

Keywords: Daclizumab, Multiple sclerosis, Patient-reported outcomes, Relapsing-remitting.

1. Introduction

While clinical trials of multiple sclerosis (MS) treatments often primarily assess outcomes such as relapse rate, brain lesions visible at magnetic resonance imaging (MRI), and disability progression (Gold and Giovannoni, 2013 and Lavery et al, 2014), it also is important to consider the impact of treatment from the patient's perspective. Patient-reported outcomes (PROs) have become important tools in clinical trials (Mitchell et al., 2005), and are frequently used as preplanned study endpoints (Deshpande et al, 2011 and US Food and Drug Administration, 2009). The US Food and Drug Administration and European Medicines Agency recognize the value of PRO instruments and support their use in clinical trials for measuring concepts best described by the patient (European Medicines Agency, 2014 and US Food and Drug Administration, 2009). Use of PROs in clinical trials can provide valuable information on the physical and psychological burden of MS and treatment benefits beyond that provided by objective and clinician-assessed clinical/radiographic outcomes. PROs also can provide information on economic/social burdens associated with MS, as well as patient preference, compliance, adherence, and satisfaction with treatment (Deshpande and Rajan, 2011; Lizán et al., 2014).

PRO instruments can be designed to assess generic health outcomes or outcomes that relate to a specific disease (Deshpande and Rajan, 2011). The 2-part EuroQol 5-Dimensions (EQ-5D) is a generic standardized utility PRO measure developed by the EuroQol Group that can be used to assess the general health status of patients (Rabin and de Charro, 2001). This PRO measure has become widely used in clinical trials across a variety of diseases (Rabin and de Charro, 2001). However, due to its generic design, it may lack sensitivity in some disease areas (Devlin and Krabbe, 2013), including MS. The 29-item Multiple Sclerosis Impact Scale (MSIS-29) is a disease-specific validated PRO (Hobart et al., 2001) used to evaluate the impact of MS on physical and psychological functioning from the patient's viewpoint. The MSIS-29 comprises a 20-item physical impact subscale (PHYS) and 9-item psychological impact subscale (PSYCH) (Hobart and Lamping, 2001). Several recent clinical studies of MS therapies have included the MSIS-29 (Gold and Giovannoni, 2013; Hupperts et al., 2015; Newsome et al., 2015).

Daclizumab high-yield process (daclizumab)1 is a humanized monoclonal antibody that specifically targets the α subunit (CD25) of the high-affinity interleukin-2 receptor commonly found on T lymphocytes, resulting in a shift of interleukin-2 signaling from T lymphocytes to other cell types whose interleukin-2 receptors lack the CD25 subunit (eg, CD56bright natural killer cells) (Martin, 2012 and Wiendl and Gross, 2013). In the pivotal dose-finding phase 2 SELECT study, patients with relapsing-remitting MS (RRMS) treated with daclizumab 150 mg subcutaneous (SC) had a lower annualized relapse rate (ARR), reduced number of brain lesions visible at MRI, and decreased risk of 12-week and 24-week confirmed disability progression versus placebo-treated patients (Gold and Giovannoni, 2013; European Medicines Agency, 2016). In SELECT, patients treated with daclizumab 150 mg SC had improvement in mean MSIS-29 PHYS score versus placebo-treated patients at week 52, and changes in MSIS-29 PHYS score were significantly different between treatment groups (Gold and Giovannoni, 2013).

Safety and efficacy of SC-administered daclizumab versus intramuscularly (IM)-administered interferon (IFN) beta-1a were explored in a recent phase 3 randomized, double-blind, active-controlled study in patients with RRMS (DECIDE; NCT01064401) (Kappos et al., 2015). Outcomes from primary analyses from DECIDE have previously been reported (Kappos and Wiendl, 2015). ARR (primary endpoint) was lower in patients receiving daclizumab 150 mg SC every 4 weeks versus patients receiving IFN beta-1a 30 mcg IM once weekly (45% relative reduction; p<0.0001) (Kappos and Wiendl, 2015). Risk of 24-week confirmed disability progression was reduced by 27% (p=0.033) in the daclizumab versus IM IFN beta-1a groups. Incidence of infections, cutaneous events, and hepatic events was higher in the daclizumab group; these events were generally managed with standard monitoring and medical interventions (Kappos and Wiendl, 2015).

The current analysis evaluated the impact of daclizumab on disease-specific/general health PROs as measured by the MSIS-29 (prespecified secondary and tertiary endpoints) and the EQ-5D (prespecified tertiary endpoint) in patients with RRMS from DECIDE.

2. Methods

2.1. Design and participants

Full details of DECIDE have previously been described (Kappos and Wiendl, 2015). In brief, 1841 patients 18–55 years of age with a confirmed diagnosis of RRMS (Polman et al., 2005) were randomly assigned (1:1) to daclizumab 150 mg SC every 4 weeks and IM placebo once weekly or IFN beta-1a 30 mcg IM once weekly (Avonex®, Biogen, Cambridge, MA, USA) and SC placebo every 4 weeks for ≥96 weeks for ≤144 weeks. Additional inclusion criteria were MRI consistent with MS, baseline Expanded Disability Status Scale score of 0–5.0, and ≥2 relapses within the previous 3 years (≥1 in year before study) or ≥1 relapse(s) and ≥1 new MRI lesion(s) within 2 years (≥1 event[s] in year before study).

Each study participant provided written informed consent. Central and local ethics committee approvals were obtained and the study was performed in accordance with the Declaration of Helsinki and the International Conference on Harmonisation Guidelines for Good Clinical Practice.

2.2. Assessments

The MSIS-29 (version 1) was administered at baseline and every 24 weeks thereafter. Each MSIS-29 item includes 5 response options that allow the patient to describe how bothered they are by the item (1= not at all, 2= a little, 3= moderately, 4= quite a bit, 5= extremely) (Hobart and Lamping, 2001; Phillips et al., 2014). Summary scores for each subscale are generated by summing individual items and then transformed onto a scale ranging from 0 to 100, with higher scores indicating a greater degree of impact on functioning from the patient's perspective (Hobart and Lamping, 2001; Phillips and Wyrwich, 2014). Outcomes explored in this analysis included the proportion of patients with clinically meaningful worsening (defined as a ≥7.5-point increase) (Phillips and Wyrwich, 2014) from baseline on the MSIS-29 PHYS at week 96 and by study visit, mean changes from baseline in MSIS-29 PHYS and PSYCH scores by study visit, and analysis of individual items for each subscale. In an analysis of data from SELECT, a ≥7.5-point worsening from baseline in MSIS-29 PHYS score was shown to be clinically meaningful (Phillips and Wyrwich, 2014). A responder definition has not been established for the MSIS-29 PSYCH.

The EQ-5D was administered at baseline and every 24 weeks thereafter. The first part of the EQ-5D consists of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) with 3 possible responses (no problems, some problems, a lot of problems). The health utility index score is calculated using scores from the 5 dimensions (Cheung et al., 2009). In general, the health utility index score typically ranges from 0.0 to 1.0, with 0 representing death and 1 representing perfect health. A negative utility score is rare, but is possible to represent health states worse than death (Devlin and Krabbe, 2013). The EQ-5D also includes a visual analog scale (VAS) that enables the respondent to self-rate their health status using a vertical scale ranging from 0 (worst imaginable state) to 100 (best imaginable state).

2.3. Statistical methods

The proportion of patients with clinically meaningful worsening, a prespecified secondary endpoint in DECIDE, was estimated using a logistic regression model adjusted for baseline MSIS-29 PHYS score, baseline Beck Depression Inventory-II (BDI-II) score, prior IFN beta use (yes, no; collected as a stratification variable in the interactive voice response system), and baseline age (≤35, >35 years). The covariates for this model were prespecified in the Statistical Analysis Plan prior to unblinding and the selection of model covariates accounted for guidelines from the European Medicines Agency and the investigators past experience in similar trials (European Medicines Agency, 2003; Phillips et al., 2014). The odds ratio (OR) for week 96 (secondary endpoint in DECIDE) has previously been reported (Kappos and Wiendl, 2015).

Mean changes from baseline in MSIS-29 PHYS and PSYCH scores between treatment groups were estimated using analysis of covariance models adjusted for baseline MSIS-29 PHYS (or PSYCH) score, baseline BDI-II score, prior IFN beta use (yes, no), and baseline age (≤35, >35 years). Patients with available baseline assessments were included in the analyses. Methods for handling missing data were consistent with recommendations from the instrument developers. For the MSIS-29 PHYS analysis, if a patient had missing data for <10/20 items, then the mean of the nonmissing items was used for the missing items (Hobart and Lamping, 2001). Missing data were imputed using a random effects model if the patient was missing ≥10/20 MSIS-29 PHYS items, or if data was missing for any other reason. Similarly, for the MSIS-29 PSYCH analysis, if a patient had missing data for <5/9 items, the mean of the nonmissing items was used for the missing items. Data was imputed using a random effects model if the patient was missing ≥5/9 items, or if data was missing for any other reason.

Individual items for both the MSIS-29 PHYS and PSYCH were analyzed post hoc. For each treatment group, we examined the items with the greatest percentage of patients reporting any bother at baseline (response options 2–5) and change from baseline in percentage of patients reporting not at all bothered (response option 1) at week 96.

Changes from baseline in EQ-5D health utility index and VAS scores between treatment groups were analyzed using an analysis of covariance with a term for treatment group and adjusted for baseline summary index or VAS scores, as appropriate; baseline BDI-II score; prior IFN beta use (yes, no); and baseline age (≤35, >35 years). If a patient was missing health utility index or EQ-5D VAS score, the missing score was estimated using a random effects model.

3. Results

A total of 1841 patients were randomized and received treatment in DECIDE; 919 received daclizumab and 922 received IM IFN beta-1a. Study withdrawal rates were similar between the treatment groups (Supplementary Figure 1). The intention-to-treat population included all randomized patients who received ≥1 dose of study medication. Mean MSIS-29 PHYS/PSYCH scores and EQ-5D health utility index/VAS scores were similar between treatment groups at baseline (Table 1).

Table 1

Demographics and baseline characteristics (ITT population).

 

Characteristic IM IFN beta-1a n=922 Daclizumab n=919
Mean (SD) age, years 36.2 (9.3) 36.4 (9.4)
Mean (SD) Beck Depression Inventory-II scorea 10.5 (8.6) 10.6 (9.1)
Prior use of IFN beta, n (%) 311 (34) 308 (34)
Median (range) EDSS score 2.25 (0.0–6.0) 2.00 (0.0–5.5)
 
EDSS score, n (%)
 <3.5 631 (68) 659 (72)
 ≥3.5 291 (32) 260 (28)
 
Mean (SD) MSIS-29 subscale scores
 MSIS-29 PHYS scoreb 21.9 (19.2) 21.5 (19.8)
 MSIS-29 PSYCH scorec 28.6 (21.1) 28.8 (21.8)
 
Mean (SD) EQ-5D scores
 EQ-5D health utility index scored 0.745 (0.22) 0.740 (0.22)
 EQ-5D visual analog scale scoree 73.7 (18.9) 74.1 (19.7)

a Interferon beta-1a, n=912; daclizumab, n=908.

b Interferon beta-1a, n=912; daclizumab, n=906.

c Interferon beta-1a, n=912; daclizumab, n=904.

d Interferon beta-1a, n=911; daclizumab, n=911.

e Interferon beta-1a, n=911; daclizumab, n=910.

EDSS, Expanded Disability Status Scale; EQ-5D, EuroQol 5-Dimensions; IFN, interferon; IM, intramuscular; ITT, intention-to-treat; MS, multiple sclerosis; MSIS-29, 29-item Multiple Sclerosis Impact Scale; PHYS, physical impact subscale; PSYCH, psychological impact subscale; SD, standard deviation.

3.1. Clinically meaningful worsening in MSIS-29 PHYS score

A lower percentage of patients in the daclizumab versus IM IFN beta-1a groups had clinically meaningful worsening in MSIS-29 PHYS score at weeks 24, 48, 72, and 96 (Fig. 1). The odds of patients experiencing a clinically meaningful worsening in MSIS-29 PHYS score were lower at both weeks 24 (OR, 0.73; 95% CI, 0.57–0.94; p=0.0132) and 96 (secondary endpoint in DECIDE; OR, 0.76; 95% CI, 0.60–0.95; p=0.0176). Covariates that were significant in the model for week 96 included baseline MSIS-29 PHYS score, baseline BDI-II score, and baseline age (≤35, >35 years; all p values <0.05; Supplementary Table 1).

Fig. 1.

Fig. 1

Percentage of patients with clinically meaningful worsening in patient-reported physical impact of MS (≥7.5-point worsening in MSIS-29 PHYS score) by study visit. Estimated from a logistic model adjusted for baseline MSIS-29 PHYS score, baseline Beck Depression Inventory-II score, prior IFN beta use (yes, no), and baseline age (≤35, >35 years). a Percent reduction in odds of clinically meaningful worsening. IFN, interferon; IM, intramuscular; MS, multiple sclerosis; MSIS-29, 29-item Multiple Sclerosis Impact Scale; PHYS, physical impact subscale..

 

3.2. MSIS-29 PHYS and PSYCH scores by study visit

Differences between the daclizumab and IM IFN beta-1a groups were observed in mean change from baseline in MSIS-29 PHYS score as early as week 24 and were maintained throughout the study period. At each study visit, the daclizumab group showed significantly greater improvement (ie, negative change) from baseline in MSIS-29 PHYS score versus the IM IFN beta-1a group, which showed no change or worsening (ie, positive change; Fig. 2a).

Fig. 2.

Fig. 2

Mean change from baseline in MSIS-29 score over time for the (a) MSIS-29 PHYS and (b) MSIS-29 PSYCH. p values represent between-treatment differences and were estimated based on an analysis of covariance model adjusting for baseline MSIS-29 PHYS (or PSYCH) score, baseline Beck Depression Inventory-II score, prior IFN beta use (yes, no), and baseline age (≤35, >35 years). Error bars represent the standard error of the mean. IFN, interferon; IM, intramuscular; MSIS-29, 29-item Multiple Sclerosis Impact Scale; PHYS, physical impact subscale; PSYCH, psychological impact subscale..

 

Mean improvements from baseline in MSIS-29 PSYCH score were observed in both treatment groups over 96 weeks, but improvements were significantly greater in the daclizumab versus IM IFN beta-1a groups at weeks 24, 48, and 96 (Fig. 2b).

3.3. Analysis of individual subscale items

Percentages of patients reporting not at all bothered (response option 1) for each MSIS-29 PHYS and PSYCH item at baseline are shown in Supplementary Fig. 2 and 3, respectively. Among the 20 MSIS-29 PHYS items, the items with the highest percentages of patients reporting some degree of bother (responses 2–5) at baseline were: do physically demanding tasks (daclizumab, 68.2%; IM IFN beta-1a, 69.0%), problems with balance (daclizumab, 67.7%; IM IFN beta-1a, 68.6%), and heavy limbs (daclizumab, 66.3%; IM IFN beta-1a, 67.6%; Supplementary Fig. 2). At week 96, daclizumab led to numerically greater improvements from baseline in proportion of patients reporting not at all bothered in 14/20 items versus IM IFN beta-1a, with greatest relative benefits in stiffness, spasms of limbs, and limitation in social/leisure activity at home (Fig. 3a). Additionally, a numerically greater percentage of daclizumab-treated patients reported an improvement of ≥1 step(s) (change in score of 1 response option, which range from 1= not at all bothered to 5= extremely bothered) for the majority of MSIS-29 PHYS items (Supplementary Table 2).

Fig. 3.

Fig. 3

Change from baseline in percentage of patients reporting not at all bothered at week 96 for the (a) MSIS-29 PHYS and (b) MSIS-29 PSYCH. IFN, interferon; IM, intramuscular; MS, multiple sclerosis; MSIS-29, 29-item Multiple Sclerosis Impact Scale; PHYS, physical impact subscale; PSYCH, psychological impact subscale..

 

For the MSIS-29 PSYCH subscale, the items with the greatest percentage of patients reporting any bother at baseline were worries related to your MS (daclizumab, 76.6%; IM IFN beta-1a, 77.9%), feeling irritable/impatient/short tempered (daclizumab, 74.7%; IM IFN beta-1a, 72.0%), and feeling anxious/tense (daclizumab, 73.1%; IM IFN beta-1a, 73.0%; Supplementary Fig. 3). At week 96, increase from baseline in percentage of patients reporting not at all bothered was numerically higher in the daclizumab versus IM IFN beta-1a groups for 6/9 items (feeling irritable/impatient/short tempered, feeling unwell, problems concentrating, lack of confidence, feeling depressed, problems sleeping [Fig. 3b]). The 3 items with the highest percentage of patients reporting any bother at baseline (worries related to your MS, feeling anxious/tense, feeling irritable/impatient/short tempered) had the highest increases from baseline in percentage of patients reporting not at all bothered at week 96 for both treatment groups. A numerically greater percentage of daclizumab-treated patients reported an improvement of ≥1 step(s) for the majority of MSIS-29 PSYCH items (Supplementary Table 2).

3.4. EQ-5D health utility index score

Over 96 weeks, mean increase from baseline in summary EQ-5D health utility index score reflected steadily improved health status for the daclizumab group, while no apparent pattern was observed in the IM IFN beta-1a group (Fig. 4a). Significantly greater improvements in the daclizumab versus IM IFN beta-1a groups were observed at week 48 (p=0.044) and week 96 (p=0.005; Fig. 4a).

Fig. 4.

Fig. 4

Mean change from baseline in the (a) EQ-5D health utility index and (b) EQ-5D VAS score. p values represent between-treatment differences and were estimated based on an analysis of covariance model adjusting for baseline EQ-5D health index (or VAS) score, baseline Beck Depression Inventory-II score, prior IFN beta use (yes, no), and baseline age (≤35, >35 years). Error bars represent the standard error of the mean. EQ-5D, EuroQol 5-Dimensions; IFN, interferon; IM, intramuscular; VAS, visual analog scale..

 

3.5. EQ-5D VAS score

Over the study period, mean improvements in EQ-5D VAS score were observed by week 24 in the daclizumab group that were sustained at week 96 (Fig. 4b). The IM IFN beta-1a group showed initial mean improvement over 48 weeks, but mean values returned to close to baseline by week 96 (Fig. 4b). Significantly greater mean improvements from baseline in the daclizumab versus IM IFN beta-1a groups were seen at week 72 (2.60 versus 1.25, respectively; p=0.022) and week 96 (2.69 versus 0.33, respectively; p<0.001).

4. Discussion

Results of these PRO measures from DECIDE suggest that treatment with daclizumab provides greater benefits in terms of reductions in the physical and psychological impact of MS and greater improvements in general health status versus IM IFN beta-1a in patients with RRMS. This study is the first to report longitudinal MSIS-29 outcomes and demonstrate improved outcomes on the MSIS-29/EQ-5D for daclizumab versus an active comparator, in addition to previously reported improved PRO endpoints versus placebo in the phase 2b SELECT study (Phillips et al., 2016).

Daclizumab-treated patients demonstrated mean improvements relative to baseline in MSIS-29 PHYS/PSYCH scores starting at week 24 that persisted over 96 weeks of treatment, while patients treated with IM IFN beta-1a had a mean decline in MSIS-29 PHYS score at week 96. These improvements from baseline were significantly different between daclizumab and IM IFN beta-1a for MSIS-29 PHYS score at all study visits evaluated and for MSIS-29 PSYCH score at 3/4 study visits. Absolute magnitude of improvements in MSIS-29 PHYS score at weeks 72 and 96 were smaller than those observed at the earlier time points in the daclizumab group. This observation is consistent with the natural history of MS in which physical function worsens over time (Confavreux and Vukusic, 2006); however, treatment with disease-modifying therapies can reduce/delay this worsening (Markowitz, 2010). Relative difference between the daclizumab and IM IFN beta-1a groups was maintained throughout the study period and increased at week 96, suggesting the patient-perceived benefit of daclizumab over IM IFN beta-1a was steady and increased over time.

Improvements in MSIS-29 PHYS/PSYCH and EQ-5D scores observed with daclizumab 150 mg SC versus IFN beta-1a 30 mcg IM in DECIDE are consistent with those reported for daclizumab 150 mg SC in SELECT (Gold and Giovannoni, 2013). Baseline mean (standard deviation) MSIS-29 PHYS scores were slightly higher in SELECT (placebo, 26.3 [22.0]; daclizumab 150 mg SC, 24.7 [20.2]) (Vollmer et al., 2013), which is consistent with other patient characteristics observed in SELECT/DECIDE (Gold and Giovannoni, 2013; Kappos and Wiendl, 2015). Treatment difference between the daclizumab 150 mg SC and placebo groups was significant for MSIS-29 PHYS score at week 52 (–1.0 [11.8] versus 3.0 [13.5], respectively; p=0.0008), where physical functioning improved in daclizumab-treated patients but worsened in placebo-treated patients (Gold and Giovannoni, 2013). Additionally, daclizumab-treated patients had improvements in EQ-5D VAS/health utility index scores versus worsening with placebo at week 52, and between-treatment group difference was significant (Gold and Giovannoni, 2013).

An analysis of individual items from the MSIS-29 PHYS in the present study found that the items that had the greatest percentage of patients in DECIDE reporting any degree of bother at baseline were do physically demanding tasks, problems with balance, and heavy limbs. It is important to note that for 11/20 items, 50% or more of patients reported they were not at all bothered at baseline, indicating a possible floor effect in the study population. However, despite this potential floor effect (ie, minimum patient-reported disease impact and therefore less room for patients to improve further) at baseline, percentage of patients reporting they were not at all bothered increased from baseline for both treatment groups across the majority of the 20 items at week 96. These results suggest that the patient-perceived treatment benefits were broadly based as opposed to concentrating in specific functional areas. These increases were numerically greater for daclizumab versus IM IFN beta-1a across 14/20 MSIS-29 PHYS items. The items that most favored daclizumab were stiffness, spasms of limbs, limitations in social/leisure activities at home, body not doing what you want it to do, and taking longer to do things. The 2 items that most favored IM IFN beta-1a were problems using transport and being stuck at home more. Percentage of patients reporting not at all bothered decreased from baseline (indicating that the symptoms and functioning in these areas on average worsened during the study period) for stiffness, spasms of limbs, and needing to go to the toilet urgently in the IM IFN beta-1a group and for being stuck at home more in the daclizumab group.

In the analysis of the individual MSIS-29 PSYCH items, both treatment groups showed increases from baseline to week 96 in percentage of patients reporting not at all bothered for the majority of items (indicating that the MS-related symptoms and functioning on averaged improved during the study period). The 3 items with the highest percentage of patients reporting any bother at baseline had the highest increases. These increases were numerically greater for the daclizumab versus IM IFN beta-1a groups for 6/9 items. Of note, problems sleeping showed the greatest difference between treatment groups in the percentage of patients who reported being not at all bothered at week 96; an increase of 5.8% from baseline was observed in the daclizumab group, but a decrease of 1.6% was observed in the IM IFN beta-1a group. A study by Bamer et al. has reported that >50% of patients with MS have difficulty sleeping (Bamer et al., 2008). Disturbances in sleep contribute to fatigue, a debilitating symptom of MS (Strober, 2015), which contributes to decreased quality of life (QoL) (Göksel Karatepe et al., 2011). Further exploration of the potential benefits of treatment with daclizumab on sleeping difficulty may be warranted.

Results of the EQ-5D were consistent with the MSIS-29 and showed that daclizumab-treated patients had greater improvements in their general health status versus patients receiving IM IFN beta-1a. The numerically small differences in mean changes from baseline in EQ-5D health utility index observed between the daclizumab and IM IFN beta-1a groups were expected because the EQ-5D is a generic instrument developed in the general population. Due to the lack of specificity for the MS population, the impact of some health problems important to QoL in patients with MS are not directly captured by the EQ-5D (Hemmett et al., 2004).

Limitations of these item-level analyses include potential ceiling and floor effects. At baseline, >50% of patients reported response option 1 (not at all bothered) for 11/20 individual MSIS-29 PHYS items, suggesting that patients in DECIDE were of limited impairment and had less room to improve from baseline. Floor effects were less pronounced for the MSIS-29 PSYCH. However, despite potential impact of ceiling effects for improvement, improvements were still observed for both treatment groups for most MSIS-29 PHYS items. Because PRO instruments such as the MSIS-29/EQ-5D are usually developed and validated at the scale level and not the item level, it is expected that more random variations are expected at the individual level versus the subscale level. Therefore, it is expected that the between-treatment comparisons at the item levels were generally not significant.

Patients with RRMS experience a spectrum of symptoms that can greatly impact their QoL. Results from PROs from DECIDE provide additional perspective on the effects of daclizumab in comparison with an active treatment such as IM IFN beta-1a. In general, daclizumab consistently showed greater benefits versus IM IFN beta-1a on both the disease-specific MSIS-29 and the EQ-5D, a measure of general health status. These results are consistent with previously reported results from DECIDE that showed that daclizumab demonstrated superior efficacy versus IM IFN beta-1a on clinical outcomes (ARR, 24-week confirmed disability progression) and radiologic outcomes (reductions in number of new T1 hypointense lesions, new/newly enlarging T2 hyperintense lesions, gadolinium-enhancing lesions) in patients with RRMS.

Contributors

Y. Liu, K. Riester, A. Lee, P. Wang, and G. Phillips participated in the design of the analyses. K. Riester and P. Wang were responsible for data analyses. Y. Liu, T. Vollmer, E. Havrdova, K. Riester, A. Lee, G. Phillips, P. Wang, and G. Sabatella participated in interpretation of the results, agreed on the content of the manuscript, reviewed drafts, provided edits, and approved the final version. The authors had full editorial control of the paper, and provided their final approval of all content.

Role of the funding source

This study was funded by Biogen and AbbVie Biotherapeutics Inc. Biogen and AbbVie Biotherapeutics Inc. participated in the design of the DECIDE phase 3 study and the conduction of the study; the post hoc analysis was completed by Biogen. Biogen and AbbVie Biotherapeutics Inc. reviewed and provided feedback on the manuscript. The study sponsors, Biogen and AbbVie Biotherapeutics Inc., provided funding for medical writing support in the development of this manuscript.

Conflict of interest

Y. Liu, K. Riester, A. Lee, G. Phillips, P. Wang, and G. Sabatellla are full-time employees of Biogen. T. Vollmer has received consulting fees from Biogen, Genentech, Novartis, Novartis Canada, Teva, Teva Canada, and Xenoport; and research funding from Acorda, Biogen, EMD Serono, Genzyme, Jensen Research, MedImmune, the National Institutes of Health, Novartis, Ono, Teva, and Vaccinex. E. Havrdova has received speaker fees and research grant support from Bayer HealthCare, Biogen, Genzyme, Merck Serono, Novartis, and Teva; compensation for advisory boards from Biogen, Genzyme, Merck Serono, Novartis, and Teva; and has been supported by PRVOUK-P26/LF1/4, project of Czech Ministry of Education.

Acknowledgments

Biogen and AbbVie Biotherapeutics Inc. provided funding for medical writing support in the development of this paper; Rebecca Jarvis from Excel Scientific Solutions (Southport, CT) wrote the first draft of the manuscript based on input from authors, and Kristen DeYoung from Excel Scientific Solutions (Southport, CT) copyedited and styled the manuscript per journal requirements. Biogen and AbbVie Biotherapeutics Inc. reviewed and provided feedback on the paper to the authors. The authors had full editorial control of the paper, and provided their final approval of all content.

Appendix A. Supplementary material

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Supplementary material

 

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References

Footnotes

a Biogen, 225 Binney Street, Cambridge, MA 02142, USA

b Department of Neurology, University of Colorado School of Medicine, Mail Stop B182, Research Complex 2, 12700 East 19th Avenue, Aurora, CO 80045, USA

c Department of Neurology, First Faculty of Medicine, Charles University in Prague, Kateřinská 1660/32, 121 08 Praha, Czechia

Correspondence to: Global Market Access, Biogen, 225 Binney Street, Cambridge, MA 02142, USA.

1 Daclizumab HYP, approved as ZINBRYTA®, has a different form and structure than an earlier form of daclizumab.


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About the Editors

  • Prof Timothy Vartanian

    Timothy Vartanian, Professor at the Brain and Mind Research Institute and the Department of Neurology, Weill Cornell Medical College, Cornell...
  • Dr Claire S. Riley

    Claire S. Riley, MD is an assistant attending neurologist and assistant professor of neurology in the Neurological Institute, Columbia University,...
  • Dr Rebecca Farber

    Rebecca Farber, MD is an attending neurologist and assistant professor of neurology at the Neurological Institute, Columbia University, in New...

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Journal Editor's choice

Recommended by Prof. Brenda Banwell

Causes of death among persons with multiple sclerosis

Gary R. Cutter, Jeffrey Zimmerman, Amber R. Salter, et al.

Multiple Sclerosis and Related Disorders, September 2015, Vol 4 Issue 5