Multiple Sclerosis Resource Centre

Welcome to the Multiple Sclerosis Resource Centre. This website is intended for international healthcare professionals with an interest in Multiple Sclerosis. By clicking the link below you are declaring and confirming that you are a healthcare professional

You are here

Assessing the impact of multiple sclerosis disease activity and daclizumab HYP treatment on patient-reported outcomes: Results from the SELECT trial

Multiple Sclerosis and Related Disorders, Volume 6, March 2016, Pages 66 - 72

Abstract

Background

The SELECT study demonstrated superior effects of daclizumab high-yield process (DAC HYP) to placebo in key endpoints in patients with relapsing and remitting multiple sclerosis (RRMS).

Objective

To assess the impact of DAC HYP and disease activity on health-related quality of life (HRQoL) using data from this study.

Methods

HRQoL was assessed at baseline, 12, 24, and 52 weeks using the Multiple Sclerosis Impact Scale (MSIS-29), the 12-items Short Form Health Survey, and the EuroQoL-5 Dimensions. An analysis of covariance model was used to compare treatment difference in change from baseline. Mixed-effects models were used to assess the impact of disability progression, relapse, treatment, and interaction between treatment and these events on HRQoL outcome.

Results

DAC HYP 150 mg resulted in significant positive impacts on HRQoL compared to placebo. It was also found to significantly reduce the adverse impact of relapse on the MSIS-29 physical scale (−12.45; p=0.0006). Relapse and disability progression were significantly associated with impaired HRQoL.

Conclusion

DAC HYP 150 mg improved HRQoL in patients with RRMS compared to placebo. The treatment benefit can be partially attributed to reduction in disease activity and attenuation of the adverse impact of relapse on HRQoL.

Highlights

  • Treatment with DAC HYP 150 mg significantly improved HRQoL in patients with RRMS.
  • This benefit is likely due to reducing the risk of relapse and disability progression.
  • MS-specific HRQoL measures better capture the treatment effect on HRQoL.

Keywords: Daclizumab high-yield process, Relapsing and remitting multiple sclerosis, MS-specific health-related quality of life measures, Multiple Sclerosis Impact Scale.

1. Introduction

Clinical studies of disease-modifying treatments (DMTs) for multiple sclerosis (MS) typically focus on physician-assessed clinical outcomes such as relapse rate and disability progression or imaging endpoints such as brain lesion burden. Castro-Borrero et al. (2012) Patients with MS report impaired health-related quality of life (HRQoL) compared with the general population (Janardhan and Bakshi, 2000, Nortvedt et al, 1999, Nortvedt et al, 2000, Putzki et al, 2009, and Rudick et al, 2007). Declines in HRQoL are multifaceted and can be related to various symptoms of MS (Noseworthy et al, 2000 and Wu et al, 2007). Thus, in addition to physician-based assessments of MS disease activity, it is also important to assess the impact of treatment from the patient’s perspective.

General HRQoL measures, such as the 12-items Short Form Health Survey (SF-12) (Ware et al., 1996) and the EuroQoL-5 Dimensions (EQ-5D), are non-disease specific measures that have been commonly used in clinical studies of DMTs for MS. Bandari et al. (2010) While these measures are applicable to all diseases and allow for comparison of HRQoL across disease states, they typically lack domains considered important to patients with MS and therefore may not be sensitive enough to capture treatment benefits. As such, several MS-specific measures of HRQoL, such as the 29-item-Multiple Sclerosis Impact Scale (MSIS-29) (McGuigan and Hutchinson, 2004 and Hobart et al, 2001), have been developed and increasingly used in clinical studies of MS along with general measures to assess treatment effects on HRQoL. However, the appropriateness of these MS-specific measures for use in clinical studies has not yet been extensively examined and thus should be further studied (Bandari et al., 2010).

Daclizumab high-yield process (DAC HYP) is an investigational DMT for patients with relapsing-remitting MS (RRMS). SELECT, a multicenter, randomized, double-blind, placebo-controlled study, has shown the superior effects of DAC HYP over placebo in the annual relapse rate (ARR) and 12-week confirmed disability progression Gold et al. (2012). The recent pivotal phase III DECIDE study further demonstrated a greater benefit of DAC HYP 150-mg in ARR compared to intramuscular interferon beta 1-a at 96 weeks (Kappos et al., 2015).

Both the SELECT and DECIDE studies have reported top-line results of DAC HYP effects on patients' HRQoL, showing that the DAC HYP 150-mg treatment significantly improved patient's HRQoL at the end of study follow-up (Gold et al, 2012 and Kappos et al, 2015). However, the temporal trend of this therapeutic effect on HRQoL has not been established; therefore in the present exploratory post-hoc analysis we examined the effects of DAC HYP on HRQoL over time using data from the SELECT study. A secondary objective was to understand the relationships between clinical outcomes (i.e., relapse occurrence and confirmed disability progression) and patients' HRQoL as measured by MS-specific and general HRQoL instruments and how these relationships were influenced by DAC HYP. Finally, the current study explored the importance of MS-specific measures of HRQoL compared to general measures of HRQoL commonly used in clinical trials.

2. Methods

2.1. The SELECT study

The SELECT study is detailed in the publication of the primary efficacy analysis Noseworthy et al. (2000). Briefly, in the SELECT trial, 621 eligible subjects were randomly assigned to receive either DAC HYP 150 mg (n=208) or 300 mg (n=209), or placebo (n=204), subcutaneously once every 4 weeks for 52 weeks. To be eligible for the study, subjects had to be 18–55 years old and diagnosed with RRMS according to 2005 McDonald criteria Polman et al. (2005). The primary endpoint was annualized relapse rate at 52 weeks. Disability progression was assessed as a 1.0 or 1.5 point increase on the EDSS from baseline EDSS≥1.0 or EDSS=0, respectively, confirmed at 12 weeks. HRQoL was considered an additional endpoint and assessed using the MSIS-29 version 1 (MSIS-29v1) (McGuigan and Hutchinson, 2004 and Hobart et al, 2001), the SF-12 (Ware et al., 1996), and the EQ-5D. (Cheung et al, 2009, EuroQol, 1990, and Hurst et al, 1994) The EDSS was assessed at baseline, 12, 20, 24, 36, 48, and 52 weeks, while the HRQoL measures were assessed at baseline, 12, 24, and 52 weeks only.

2.2. Assessments

The MSIS-29v1 is an MS-specific HRQoL measure designed to assess the physical and psychological impact of MS (McGuigan and Hutchinson, 2004 and Hobart et al, 2001). It comprises a 20-item subscale measuring physical impact and a nine-item subscale measuring psychological impact. Hobart et al. (2001) Scores on each subscale range from 0 (best) to 100 (worst). The SF-12 is a general (non-disease specific) measure of patients' HRQoL, with results expressed in terms of two aggregate scores: the PCS (physical component summary) and MCS (mental component summary), both scored 0–100, with higher scores indicating better health Ware et al. (1996). Another general measure, the EQ-5D, consists of five sets of three statements (levels) each, pertaining to specific health states (mobility, self-care, pain, usual activities, and anxiety/depression) (Cheung et al, 2009, EuroQol, 1990, and Hurst et al, 1994). The scores range from −0.59 (worse than death) to 1.0 (perfect health) using the weights derived from the populations in the United Kingdom. The EQ-5D also includes a visual analogue scale (VAS), a 20-cm vertical scale with endpoints labeled “Best imaginable health state” and “Worst imaginable health state.” It provides a single numeric measure of overall health status, with scores ranging from 0 (worst) to 100 (best) Cheung et al. (2009).

There was not a single a priori way of categorizing or coding disability progression and relapse in this analysis. As a result, in line with the exploratory nature of this analysis, each of them was coded in two different ways, and used in different outcome models. The first, confirmed disability progression coding, was defined as a 1.0-point change in EDSS for those with baseline EDSS>0, or a 1.5-point change for those with baseline EDSS=0, that was sustained for at least 12 weeks (yes vs. no). The second, time since confirmed disability progression, was coded as an ordinal variable: no progression, 0–8 days since start of progression, and ≥9 days since start of progression. Such a cutoff was used because a considerable number of the confirmed progressions occurred within 8 days prior to a HRQoL assessment. Relapses were also coded in two ways: first, the cumulative number of relapses occurring during the study period, and second as a five-level, ordered-categorical variable, capturing the time since the beginning of their most recent relapse (0–29 days, 30–60 days, 61–90 days, 91–180 days, 181+ days). Since patients with a relapse between 30–180 days and those with ≥181 days accounted for similar changes in all HRQoL measures in the univariate analyses, except for the SF-12 MCS, this covariate was re-coded to combine these two relapse groups into one category creating a dichotomous variable (0–29 days or 30+days) for subsequent modeling.

In the univariate analyses, whether patients had disability progression for ≤8 days or none at all did not make any marked difference in their respective change scores in any of the measures, except for the EQ-5D VAS. This suggests that the adverse impact on HRQoL caused by disability progression may gradually increase and last for a long-term, which contrasts with the more immediate effect caused by relapse. Because of this, a simple binary yes vs. no disability progression was used for subsequent models.

2.4. Statistical analysis

Scores for each HRQoL measure were calculated according to the standard scoring methods (Hobart et al, 2001 and Cheung et al, 2009). Analysis of change from baseline at each visit by treatment was conducted in all 600 patients in the intent-to-treat (ITT) population, derived from the 621 patients enrolled in the study, with the elimination of 21 patients from a single study site who were prospectively excluded from the ITT population due to systematic misdosing at the site Havrdova et al. (2014). Change in scores from baseline for each measure were estimated and summarized by treatment group and visit. Analysis of covariance (ANCOVA) models adjusting for baseline scores were used to compare difference in mean change from baseline between treatment groups and placebo. Missing data were not imputed in the analyses.

To assess the impact of clinical MS disease activity on patients' HRQoL, while controlling for other relevant covariates, a post-hoc exploratory analysis was conducted for each HRQoL measure using linear mixed-effects regression models (PROC MIXED in SAS®), with a random intercept and slope for each patient. This model used a longitudinal data set to investigate the effects of time-dependent clinical MS disease activities (i.e., relapses and disability progression) and the interactions of treatment and these activities on change in HRQoL, controlling for patient and disease characteristics at baseline.

The final mixed-effects regression models were developed based on the following statistical steps. First, potential baseline patient and disease characteristics were individually examined in models that included treatment and time, which provided justification for inclusion in the multivariate model (based on p-value <0.10). Key baseline factors tested in the models included, but were not limited to, HRQoL score, age, gender, EDSS, disease duration, number of relapses prior to study, McDonald criteria, prior MS treatments, number/presence of gadolinium-enhancing lesions, number of T2 lesions/volume, and number of T1 lesions/volume. Next, the time-dependent variables were also tested in the same way as done for baseline factors. These included the alternate version of representing disability progression and relapse. To examine whether treatment modified the impact of these time-dependent disease events, interaction terms of treatment and each of these variables were tested in the models. Finally, all qualified predictors, identified from the previous steps, were included in the multivariate models along with treatment and visit timing. The models were then trimmed down to keep significant predictors by removing non-significant predictors one at time. All analyses were performed using SAS® version 9.2.

3. Results

A total of 600 subjects (n=196 for placebo; n=201 for DAC HYP 150 mg; and n=203 for DAC HYP 300 mg) were included in the analysis. Descriptive statistics of baseline patient and disease characteristics and HRQoL domain scores are summarized in Table 1. Overall, baseline demographics and HRQoL scores for the treatment groups were examined and found to be similar among the three groups.

Table 1 Patient characteristic at baseline.

Placebo (n=196) DAC 150mg (n=201) DAC 300mg (n=203)
Age, mean (SD) 36.9 (9.0) 35.2 (9.1) 35.4 (8.6)
Female (%) 123 (63) 136 (68) 132 (65)
Race (%)
 White 189 (96) 195 (97) 194 (96)
 Asian 7 (4) 6 (3) 9 (4)
Time since diagnosis (years), mean (SD) 4.2 (5.3) 4.5 (5.0) 3.8 (4.0)
Number of relapses in the past year prior to randomization, mean (SD) 1.3 (0.6) 1.4 (0.7) 1.3 (0.7)
EDSS, mean (SD) 2.7 (1.2) 2.8 (1.1) 2.6 (1.2)
Prior disease-modifying therapy, n (%)a 47 (24) 50 (25) 47 (24)
PRO measures, mean (SD)
 MSIS-29 physical 26.3 (22.0) 24.7 (20.2) 24.0 (19.5)
 MSIS-29 psychological 29.5 (22.5) 28.6 (21.5) 29.6 (20.7)
 SF-12 PCS 42.5 (10.0) 42.9 (9.9) 43.1 (9.0)
 SF-12 MCS 46.4 (10.2) 46.1 (11.5) 45.5 (11.0)
 EQ-5D utility 0.73 (0.2) 0.73 (0.22) 0.74 (0.2)
 EQ-5D VAS 71.1 (18.3) 72 (17.4) 72.1 (18.1)

a Disease-modifying multiple sclerosis therapies included: azathioprine, cyclophosphamide, dimethyl fumarate, fingolimod, fumarate disodium, fumaric acid, glatiramer acetate, human immunoglobulin G, immunoglobulin, interferon α, interferon β-1b, interferon β-1a, laquinimod, methotrexate, mitoxantrone, natalizumab, other antineoplastic agents, other therapeutic products, plasmapheresis, teriflunomide, and thymostimulin.

DAC HYP, daclizumab high-yield process; EDSS, Expanded Disability Status Scale; EQ-5D, EuroQol 5 Dimensions; MCS, mental component summary; MSIS-29, Multiple Sclerosis Impact Scale; PCS, physical component summary; PRO, patient-reported outcome; SD, standard deviation; SF-12, 12-Item Short-Form Health Survey; VAS, visual analog scale.

Change from baseline on each HRQoL measure is shown in Fig. 1(A–F) by treatment and visit with comparisons between the treatment groups and placebo. The DAC HYP 150-mg treatment group was statistically significantly better than the placebo group on: (1) the MSIS-29v1 physical impact scale at 12, 24, and 52 weeks; (2) the MSIS-29v1 psychological impact scale at 24 weeks; (3) the SF-12 PCS and MCS at 24 and 52 weeks; and (4) the EQ-5D Health Utility Index and VAS at 24 and 52 weeks. For the DAC HYP 300-mg treatment group, change at each visit from baseline appeared more favorable compared to placebo across all measures, but only the contrast at 52 weeks on the EQ-5D VAS assessment was statistically significantly better than the placebo treated group.

Fig. 1

Fig. 1 Change from Baseline by Treatment and Visit (A) MSIS-29 Physical (B) MSIS-29 Psychological (C) SF-12 PCS (D) SF-12 MCS (E) EQ-5D Health Utility (F) EQ-5D VAS. CI, confidence interval; EQ-5D, EuroQol 5 Dimensions; MCS, mental component summary; MSIS-29, Multiple Sclerosis Impact Scale; PCS, physical component summary; SF-12, 12-Item Short-Form Health Survey; VAS, visual analog scale. *p<0.05 compared to placebo. **p<0.01 compared to placebo.

Results of the post-hoc exploratory analysis are displayed in Table 2. Both occurrence of relapses and initiation of 12-week confirmed disability progressions were found to be significantly associated with deterioration in all HRQoL measures after controlling for relevant baseline covariates. The impact of relapses was assessed based on both the timing and number of relapses at the time of a given HRQoL assessment; the former (i.e., time since last relapse within 29 days) was found to have a significant (p<0.05) adverse impact on HRQoL, on all measures. The number of relapses experienced by patients was significantly associated with impaired HRQoL on the MSIS-29v1-physical scale, such that those with ≥2 relapses were 7.1 points worse than those with none (p<0.05), and the EQ-5D health utility score such that those with ≥2 relapses were 0.1 points worse than those with none (p<0.05). Exploratory analysis with both disability progression variables showed that experiencing disability progression also had a significant negative impact on HRQoL across all measures (Table 2). The binary disability progression (yes vs. no) was significant in every measure modeled except for the EQ-5D VAS where the alternate time since progression variable was significant.

Table 2 Results of post-hoc multivariate analyses.

Variable Level Patient-reported outcomes
MSIS-29 physical a MSIS-29 psychological b SF-12 PCS c SF-12 MCS d EQ-5D utility e EQ-5D VAS f
β (95% CI) β (95% CI) β (95% CI) β (95% CI) β (95% CI) β (95% CI)
Treatment arm DAC HYP 150 mg vs. placebo −2.75 (−4.65, −0.86)** −2.39 (−4.76, −0.02)** NS 1.34 (−0.01, 2.69)* 0.02 (0,0.05)* NS
DAC HYP 300 mg vs. placebo NS NS NS NS NS NS
Time since last relapse 0–29 vs. 30+ days 17.6 (12.65, 22.56)** 5.72 (2.22, 9.21)** −5.74 (−7.59, −3.9)** NA −0.09 (−0.14, −0.04)** −7.26 (−11.42, −3.09)**
0–29 vs. 181+ days NA NA NA −2.72 (−5.03, −0.41)** NA NA
30–90 vs. 181+ days NA NA NA −2.02 (−3.53, −0.51)** NA NA
91–180 vs. 181+ days NA NA NA −0.72 (−1.61, 0.17) NA NA
Cumulative number of relapse observed in the trial 0 vs. ≥2 −7.1 (−11.19, −3.02)** NS NS NS 0.1 (0.03, 0.16)** NS
1 vs. ≥2 −5.49 (−9.42, −1.56)** NS NS NS 0.09 (0.02, 0.15)** NS
Treatment arm*Time since last relapse DAC HYP 150 mg vs. Placebo & 0–29 vs. 30+ days −12.45 (−19.52, −5.37)** NS NS NS NS NS
DAC HYP 300 mg vs. Placebo & 0–29 vs. 30+ days −7.68 (−15.22, −0.14)** NS NS NS NS NS
Confirmed disability progression Yes vs. No 4.63 (7.34, 1.92)** 3.96 (0.89, 7.03)** −2.34 (−3.92, −0.75)** −1.78 (−3.77, 0.22)* −0.07 (−0.11, −0.03)** NA
0–8 days vs. No progression NA NA NA NA NA −7.88 (−12.82, −2.93)**
9+ days vs. No progression NA NA NA NA NA −4.51 (−8.22, −0.79)**

a The final model is also controlled for other significant covariates, including time(visit), baseline value, race, and prior use of disease modifying drug.

b The final model is also controlled for other significant covariates, including time(visit), baseline value, and race.

c The final model is also controlled for other significant covariates, including treatment arm, time(visit), baseline value, age, time since diagnosis, and number of relapse prior to study entry.

d The final model is also controlled for other significant covariates, including time(visit), baseline value, prior use of disease modifying drug, and baseline McDonald criteria.

e The final model is also controlled for other significant covariates, including time(visit), baseline value, race, and number of relapse prior to study entry.

f The final model is also controlled for other significant covariates, including treatment arm, time(visit), time*treatment arm, and baseline value.

* p<0.10.

** p<.05.

CI, confidence interval; EQ-5D, EuroQol 5 Dimensions; MCS, mental component summary; MSIS-29, Multiple Sclerosis Impact Scale; NA, not applicable; NS, not significant at p<0.1; PCS, physical component summary; SF-12, 12-Item Short-Form Health Survey; VAS, visual analog scale.

The final area of interest in the multivariate models is that of treatment effects on patient reported HRQoL. Results of the post-hoc exploratory analysis indicated significant treatment effects (p<0.05) on the MSIS-29v1 physical and psychological subscales with patients treated with 150 mg of DAC HYP, reporting significantly less physical and psychological impact than those treated with placebo, even after accounting for the effects of reducing MS disease activities (Table 2), presumed to be treatment benefits. Such a significant treatment effect, however, was not observed in general non-disease specific measures (SF-12 and EQ-5D), after adjusting for the treatment benefits mediated through the effects of MS disease activities. The regression results also indicated a significant interaction term for treatment and time since last relapse on the MSIS-29v1 physical scale. The magnitude of adverse impact due to having a recent relapse was significantly reduced in patients receiving either DAC HYP 150 mg (−12.45; p=0.0006) or DAC HYP 300 mg (−7.68, p<0.0459), compared to placebo.

4. Discussion

MS is the leading cause of non-traumatic disability in young adults. HRQoL has been reported to be significantly worse in patients with MS, compared to the general population and even to patients with chronic illnesses, such as diabetes and congestive heart failure Wu et al. (2007). Deterioration in HRQoL, especially in the physical dimensions, has also been reported to be highly associated with the increased risk of losing employment status (Jones et al., 2013), an essential part of life to this population due to the early onset of disease at age of 20–30. As there is still no cure for MS, maintaining or improving patients' HRQoL has increasingly become an important goal in the treatment of patients with MS. This study aimed to assess the effects on HRQoL of DAC HYP vs. placebo over time. Results of the analysis show that treatment with DAC HYP 150 mg resulted in significant positive impacts on both the physical and psychological dimensions of HRQoL compared to placebo. Such treatment benefits, particularly to the physical domain, were apparent at 24 weeks and maintained at the 52 week study point and such findings are consistent regardless of whether the assessment is made with an MS-specific or general measures of HRQoL. Positive effects on HRQoL were also found in the DAC HYP 300-mg group relative to placebo, but as with the primary clinical outcomes, this 300-mg dosing regimen did not provide additional benefits compared to the 150-mg dosing on HRQoL endpoints Gold et al. (2013).

A published analysis using the same data from the SELECT trial suggested that an increase of ≥7.5 points on the MSIS-29v1 physical scale can be considered a clinically-meaningful deterioration Phillips et al. (2014). When this threshold was used, the proportions of patients experiencing a clinically-meaningful physical deterioration at 12, 24, and 52 weeks were reported to be significantly lower (p<0.01) with the DAC HYP 150-mg dosing regimen (12%, 14%, and 20%, respectively) than with the DAC HYP 300-mg regimen (18%, 24%, and 27%) or placebo (17%, 24%, and 28%) Phillips et al. (2014). Such findings further support the benefit of treatment with DAC HYP 150 mg in HRQoL among patients with RRMS. Unlike the primary analysis of the efficacy data, where the DAC HYP 300-mg dose was very similar to the 150-mg dose (Gold et al., 2013), the former dosing looks worse in the present analyses based on HRQoL endpoints. We cannot say for certain why the 150-mg dose appears better based on HRQoL endpoints, as the safety profile also looks very similar between both doses Gold et al. (2013). But these analyses make it appear as though patients simply feel better on the lower dose than on the higher dose or placebo. Further investigation would be needed to explore the underlying causes.

The treatment benefits of DAC HYP on HRQoL are likely attributable to its superior effects in reducing the risks of relapse and rate of disability progression over placebo. This exploratory analysis showed that both relapse and 12-week confirmed disability progression were found to have significant negative impact on all the HRQoL measures under study. Thus, the ability of a DMT to effectively reduce the risk of relapse or disability progression should proportionately help maintain or improve patients' HRQoL. The strong associations between MS disease activities and impaired HRQoL observed in this study have been well documented in the literature (Putzki et al, 2009, Healy et al, 2012, Hemmett et al, 2004, Orme et al, 2007, Kern et al, 2009, Lobentanz et al, 2004, and Naci et al, 2010). However, a novel finding of this analysis, which has not yet been reported, is that the detrimental impact of a recent relapse on the physical functioning can potentially be beneficially modified by DAC HYP. The magnitude of adverse physical impact caused by a relapse was significantly smaller in patients receiving DAC HYP, especially with the 150-mg dosing. This treatment benefit may be due to a reduction in the severity of relapses when treated with DAC HYP Kappos et al. (2015). Additional studies are needed to confirm this finding and identify the underlying factors contributing to such an effect modification.

The study findings also show that there are additional significant treatment benefits (p<0.05) in HRQoL with DAC HYP 150-mg compared to placebo, after accounting for effects of reduced MS disease activities, possibly by improving baseline MS symptoms.. These additional treatment HRQoL benefits, however, were observed only in the MSIS-29v1 physical and psychological scales not in other general HRQoL measures used in this study. This finding, together with the effect modification observed only in the physical scale of the MSIS-29v1, seems to indicate that MS-specific measures of HRQoL are more sensitive detectors of treatment benefits than other measures. Although to date, the MS research community has not fully embraced the use of disease specific HRQoL measures such as the MSIS-29v1, this study is an important example of the benefit of using this measure. Together with similar findings for other MS-specific measures, such as MSQoL-54 (Knezevic et al, 2015 and Özakbas et al, 2007), this study provides a strong argument for the use of such MS-specific measures in clinical research, over and above that of general HRQoL measures. The research community has increasingly seen the value of using such measures, as is evidenced by their growing use in the clinical trials as well as in the clinical practice Jones et al. (2013). We can now add this study's demonstration to the growing basis, supporting the use of such disease specific HRQoL measures. Namely, the finding that the MSIS-29v1 has more sensitivity to changes in HRQoL caused by relapse and disability progression and, more importantly, is able to detect treatment benefits which were not captured by general measures.

The key limitations of the post-hoc analyses include the possibility that our models over fit the data given the sample size (n=600) and the small number of MS clinical events observed in the SELECT trial. As an exploratory analysis to improve our understanding of factors that may affect HRQoL among patients with RRMS and generate ideas/hypotheses for future research, we did not limit the number of parameters tested in the models, nor adjust statistical significance criteria for multiple comparisons. Another key limitation is the short follow-up duration in the SELECT trial, providing no information on the effects of DAC HYP on HRQoL over a longer term. Data from the SELECTION trial, an extension randomized-controlled trial of the SELECT, are of limited usefulness to inform the durability of effects of DAC HYP beyond one year, due to its study design in re-assigning the placebo-treated subjects to receive DAC HYP (i.e., no placebo-treated subjects) and a small number of subjects receiving DAC HYP continuously. Giovannoni et al. (2014) However, the recent data from the DECIDE trial have shown that mean change from baseline, as measured by the MSIS-29 and EQ-5D, was statistically significantly better with DAC HYP 150-mg than with intramuscular interferon beta 1-a at both 48 and 96 weeks. Kappos et al. (2015) This clearly indicates that the benefits of DAC HYP 150 mg in HRQoL can be sustained beyond one year.

HRQoL has increasingly become an important endpoint in clinical trials of DMTs for MS, to evaluate patient-experience and reported treatment effects. This analysis of HRQoL data from the 1-year SELECT trial showed that treatment with DAC HYP 150 mg results in significant improvement in HRQoL among patients with RRMS compared to placebo over 52 weeks, whether MS-specific or general HRQoL measures are used. Its benefits in HRQoL compared to placebo can be partially attributed to a reduction in the frequency of relapse and disability progression, as they were found to be highly associated with impaired HRQoL from our post-hoc analysis, as well as potentially to its attenuation of the adverse impact of individual relapses on HRQoL. Finally, our analysis suggests that treatment benefits on HRQoL would be better captured using a disease-specific HRQoL measure, than general health status or general measures. Future clinical trials of MS considering HRQoL as an endpoint would be better served using MS disease specific measures, such as the MSIS-29.

Funding

This study was funded by Biogen.

Conflict of interest

Shien Guo, Randall Bender and Irina Proskorovsky are employees of Evidera who were paid consultants by Biogen in connection with this study and development of this manuscript. Glenn Phillips is an employee of Biogen. Eva Havrdová is affiliated with Charles University in Prague, Czech Republic. Timothy Vollmer is affiliated with the University of Colorado, in Aurora, Colorado. All authors reviewed and approved of the final manuscript.

References

  • Bandari et al., 2010 D.S. Bandari, T.L. Vollmer, B.O. Khatri, et al. Assessing quality of life in patients with multiple sclerosis. Int. J. MS Care. 2010;12(1):34-41 Crossref
  • Castro-Borrero et al., 2012 W. Castro-Borrero, D. Graves, T.C. Frohman, et al. Current and emerging therapies in multiple sclerosis: a systematic review. Ther. Adv. Neurol. Disord.. 2012;5(4):205-220 Crossref
  • Cheung et al., 2009 Cheung, K.O., Oppe, M. Rabin, M.R., 2013. EQ-5D User Guide: Basic Information on How to Use EQ-5D. 2009, 〈http://www.euroqol.org/fileadmin/user_upload/Documenten/PDF/User_Guide_v2_March_2009.pdf〉 (accessed 14.02.13).
  • EuroQol, 1990 G. EuroQol. EuroQol – a new facility for the measurement of health-related quality of life. Health Policy. 1990;16(3):199-208
  • Giovannoni et al., 2014 G. Giovannoni, R. Gold, K. Selmaj, et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECTION): a multicentre, randomised, double-blind extension trial. Lancet Neurol.. 2014;13(5):472-481 Crossref
  • Gold et al., 2012 Gold R., Giovannoni G., Selmaj K., et al., 2012. A randomised, double-blind, placebo-controlled trial of daclizumab HYP in relapsing-remitting multiple sclerosis. Submitted.
  • Gold et al., 2013 R. Gold, G. Giovannoni, K. Selmaj, et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial. Lancet. 2013;381(9884):2167-2175 Crossref
  • Havrdova et al., 2014 E. Havrdova, G. Giovannoni, D. Stefoski, et al. Disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with daclizumab high-yield process in the SELECT study. Mult. Scler.. 2014;20(4):464-470 Crossref
  • Healy et al., 2012 B.C. Healy, I.R. Degano, A. Schreck, et al. The impact of a recent relapse on patient-reported outcomes in subjects with multiple sclerosis. Qual. Life Res.. 2012;21(10):1677-1684 Crossref
  • Hemmett et al., 2004 L. Hemmett, J. Holmes, M. Barnes, et al. What drives quality of life in multiple sclerosis?. QJM. 2004;97(10):671-676 Crossref
  • Hobart et al., 2001 J. Hobart, D. Lamping, R. Fitzpatrick, et al. The Multiple Sclerosis Impact Scale (MSIS-29): a new patient-based outcome measure. Brain. 2001;124(Pt 5):962-973 Crossref
  • Hurst et al., 1994 N.P. Hurst, P. Jobanputra, M. Hunter, et al. Validity of Euroqol – a generic health status instrument--in patients with rheumatoid arthritis. Economic and Health Outcomes Research Group. Br. J. Rheumatol.. 1994;33(7):655-662
  • Janardhan and Bakshi, 2000 V. Janardhan, R. Bakshi. Quality of life and its relationship to brain lesions and atrophy on magnetic resonance images in 60 patients with multiple sclerosis. Arch. Neurol.. 2000;57(10):1485-1491
  • Jones et al., 2013 K.H. Jones, D.V. Ford, P.A. Jones, et al. The physical and psychological impact of Multiple Sclerosis using the MSIS-29 via the web portal of the UK MS Register. PLoS One. 2013;8(1):e55422 Crossref
  • Kappos et al., 2015 Kappos, L., Selmaj, K., Arnold, D.L., et al., 2015. Daclizumab high-yield processreduced disabling relapses and the rate of severe/serious relapses: post hoc analyses of the SELECT and DECIDE Studies. The 1st Congress of the European Academy of Neurology, June 20–23, 2015, Berlin, Germany.
  • Kappos et al., 2015 L. Kappos, K. Selmaj, D.L. Arnold, et al. Daclizumab HYP versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N. Engl. J. Med.. 2015;373(15):1418-1428
  • Kern et al., 2009 S. Kern, W. Schrempf, H. Schneider, et al. Neurological disability, psychological distress, and health-related quality of life in MS patients within the first three years after diagnosis. Mult. Scler.. 2009;15(6):752-758 Crossref
  • Knezevic et al., 2015 T. Knezevic, L. Konstantinovic, S. Rodic, et al. Validity and reliability of the Serbian version of Patient-Reported Impact of Spasticity Measure in multiple sclerosis. Int. J. Rehabil. Res.. 2015;3(38):199-205 Crossref
  • Lobentanz et al., 2004 I.S. Lobentanz, S. Asenbaum, K. Vass, et al. Factors influencing quality of life in multiple sclerosis patients: disability, depressive mood, fatigue and sleep quality. Acta Neurol. Scand.. 2004;110(1):6-13 Crossref
  • McGuigan and Hutchinson, 2004 C. McGuigan, M. Hutchinson. The multiple sclerosis impact scale (MSIS-29) is a reliable and sensitive measure. J. Neurol. Neurosurg. Psychiatry. 2004;75(2):266-269
  • Naci et al., 2010 H. Naci, R. Fleurence, J. Birt, et al. The impact of increasing neurological disability of multiple sclerosis on health utilities: a systematic review of the literature. J. Med. Econ.. 2010;13(1):78-89 Crossref
  • Nortvedt et al., 1999 M.W. Nortvedt, T. Riise, K.M. Myhr, et al. Quality of life in multiple sclerosis: measuring the disease effects more broadly. Neurology. 1999;53(5):1098-1103
  • Nortvedt et al., 2000 M.W. Nortvedt, T. Riise, K.M. Myhr, et al. Performance of the SF-36, SF-12, and RAND-36 summary scales in a multiple sclerosis population. Med. Care. 2000;38(10):1022-1028 Crossref
  • Noseworthy et al., 2000 J.H. Noseworthy, C. Lucchinetti, M. Rodriguez, et al. Multiple sclerosis. N. Engl. J. Med.. 2000;343(13):938-952 Crossref
  • Orme et al., 2007 M. Orme, J. Kerrigan, D. Tyas, et al. The effect of disease, functional status, and relapses on the utility of people with multiple sclerosis in the UK. Value Health. 2007;10(1):54-60 Crossref
  • Özakbas et al., 2007 S. Özakbas, B. Akdede, G. Kösehasanogullari, et al. Difference between generic and multiple sclerosis-specific quality of life instruments regarding the assessment of treatment efficacy. J. Neurol. Sci.. 2007;256(1):30-34
  • Phillips et al., 2014 G.A. Phillips, K.W. Wyrwich, S. Guo, et al. Responder definition of the Multiple Sclerosis Impact Scale physical impact subscale for patients with physical worsening. Mult. Scler.. 2014;20(13):1753-1760 Crossref
  • Polman et al., 2005 C.H. Polman, S.C. Reingold, G. Edan, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann. Neurol.. 2005;58(6):840-846 Crossref
  • Putzki et al., 2009 N. Putzki, J. Fischer, K. Gottwald, et al. Quality of life in 1000 patients with early relapsing-remitting multiple sclerosis. Eur. J. Neurol.. 2009;16(6):713-720 Crossref
  • Rudick et al., 2007 R.A. Rudick, D. Miller, S. Hass, et al. Health-related quality of life in multiple sclerosis: effects of natalizumab. Ann. Neurol.. 2007;62(4):335-346 Crossref
  • Ware et al., 1996 J. Ware Jr., M. Kosinski, S.D. Keller. A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med. Care. 1996;34(3):220-233 Crossref
  • Wu et al., 2007 N. Wu, S.L. Minden, D.C. Hoaglin, et al. Quality of life in people with multiple sclerosis: data from the Sonya Slifka Longitudinal Multiple Sclerosis Study. J. Health Hum. Serv. Adm.. 2007;30(3):233-267

Footnotes

a Biogen, 300 Binney Street, Cambridge, MA 02142, United States

b Evidera, 430 Bedford St. Suite 300 Lexington Office Park, Lexington, MA 02420, United States

c Evidera, 7101 Wisconsin Ave., Suite 1400, Bethesda, MD 20814 United States

d Charles University in Prague, Ovocný trh 3-5 Prague 1, 116 36, Prague, Czech Republic

e Evidera, 7575 Trans-Canada Highway Suite 500, St-Laurent, Quebec, Montreal, Canada H4T 1V6

f University of Colorado School of Medicine, Anschutz Medical Campus, Department of Neurology, Academic Office 1, Mail Stop B-185, 12631 East 17th Avenue, Aurora, CO 80045, United States

Correspondence to: Biogen Value Based Medicine, 133 Boston Post Road, Weston, MA 02493, USA.


Search this site

Stay up-to-date with our monthly e-alert

If you want to regularly receive information on what is happening in MS research sign up to our e-alert.

Subscribe »

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...

This online Resource Centre has been made possible by a donation from EMD Serono, Inc., a business of Merck KGaA, Darmstadt, Germany.

Note that EMD Serono, Inc., has no editorial control or influence over the content of this Resource Centre. The Resource Centre and all content therein are subject to an independent editorial review.

The Grant for Multiple Sclerosis Innovation
supports promising translational research projects by academic researchers to improve understanding of multiple sclerosis (MS) for the ultimate benefit of patients.  For full information and application details, please click here

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