Abstract
Background: The recent randomized, controlled trial of interferon-β1b (IFN-β1b) in 718 patients with secondary progressive MS (SP-MS) demonstrated a significant effect on the development of disability as evaluated by the physician. Its effect on patient-reported health-related quality of life (HrQoL) is reported herein.
Methods: In this multicenter, double-blind, randomized, placebo-controlled trial, outpatients with SP-MS scoring between 3.0 and 6.5 on the Expanded Disability Status Scale received either 8 × 106 IU of IFN-β1b or placebo for up to 3 years. A range of outcomes was measured, including HrQoL, which was assessed using the Sickness Impact Profile (SIP), a self-report questionnaire validated for use in MS. Measurements were undertaken at baseline and at 6-monthly intervals thereafter for 36 months.
Results: A slight positive effect on the HrQoL of the IFN group in comparison with the placebo group was found, which reached significance in the physical scale of the SIP at 6 and 12 months and at last visit. There was moderate correlation between physician-assessed evaluation of change and patient-reported change.
Conclusions: IFN-β1b may delay sustained deterioration in patient-reported HrQoL in SP-MS. Methods of interpreting change in HrQoL are currently insufficiently developed to determine how clinically important these changes are for this population.
Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the November 27 issue to find the title link for this article.
β-Interferon (IFNβ) is the first effective treatment for altering the natural course of relapsing–remitting MS (RR-MS).1-3⇓⇓ More recently, IFN-β1b has also shown to be effective in the secondary progressive (SP) form of the disease.4 The outcomes measured in trials of IFNβ have, in the main, focused on clinical endpoints such as relapse rate and assessments of disability by the physician (e.g., Kurtzke’s Expanded Disability Status Scale [EDSS]) and para-clinical aspects of disease (e.g., MRI). These physician-oriented measures, however, offer just one perspective, and it has been suggested that evaluation of outcome based solely on these measures may be of limited usefulness because it does not consider the patient’s viewpoint.5
Taking into account the patient’s perspective is particularly relevant when evaluating the efficacy of IFN therapy since there is still no cure for MS and patients have to be treated on a long-term basis. Treatment is associated with a number of side effects, which have been shown to impact broadly on health-related quality of life (HrQoL).6 These issues are of considerable concern to MS patients and health care professionals and may markedly influence their decision in undertaking, or prescribing, drug therapy. Perhaps even more importantly, evaluation of the impact of interventions on HrQoL is increasingly considered fundamental to the development of clinical guidelines, determining cost-effectiveness,7 and providing guidance for the commissioning of services.8 Decisions made at this broader level will impact on the utilization of different therapeutic interventions by individuals.9
Broadly, there are three different approaches to measuring HrQoL: 1) generic instruments, such as the 36-item Short Form Health Survey Questionnaire (SF-36)10 and the Sickness Impact Profile (SIP)11; 2) disease-specific instruments such as the MS Quality of Life-54 (MSQOL-54),12 MS Quality of Life Inventory (MSQLI),13 and Functional Assessment of MS14; 3) utility-based instruments, which can be used for cost-utility analyses, such as the EuroQol–5 Dimensions (EQ-5D).15
Generic instruments enable comparisons with other conditions and with the general population. Disease-specific instruments have the potential to be more sensitive to changes from interventions or disease progression; however, such instruments may not be available for all conditions. Before the MSQOL-54 and the MSQLI were published in 1995, no validated disease-specific HrQoL instrument was available for MS; as a consequence, the majority of studies to date have used either generic or utility instruments. Studies on the impact of interventions on HrQoL in MS are sparse and focus mainly on rehabilitation settings.16,17⇓
The SIP has a number of advantages for use as a generic HrQoL instrument in MS. There is extensive evidence to support its reliability and validity in a range of conditions18,19⇓ including MS,20-22⇓⇓ and it has been validated in multiple languages.23 Little attention has been paid to determining its responsiveness, however, apart from one short-term study in RR-MS.20 No responsiveness data are available for the SIP in a controlled setting comparing interventions for MS.
We report on HrQoL in a large sample of patients enrolled in the European Study Group Trial of Interferon-β1b in Secondary Progressive MS.4
Methods.
Study design.
The design of this study has been reported in detail elsewhere.4 In brief, this European multicenter, double-blind, placebo-controlled study investigated the effectiveness of IFN-β1b in the treatment of SP-MS. Patients with a clinically or laboratory-supported definite diagnosis of MS, in the secondary phase of the disease,4 and scoring between 3.0 and 6.5 on the EDSS, were randomly assigned to either the IFN group (n = 360) or the placebo group (n = 358). Patients injected 4 × 106 IU of IFN-β1b or placebo subcutaneously for the first 2 weeks, thereafter increasing their dose to 8 × 106 IU of IFN-β1b or placebo every other day.
The primary outcome measure was the time from baseline to confirmed progression on the EDSS, as determined by an increase of at least 1.0 EDSS point (0.5 point if the baseline EDSS was 6.0 or 6.5), confirmed at a second visit at least 70 days apart. The secondary outcome measures were time to becoming wheelchair bound, relapse rate (frequency, duration, severity), and T2 lesion volume and newly active lesions in the frequent MR subgroup. Tertiary endpoints included MS-related steroid use, frequency of hospital admissions, and a global evaluation of the neurologist’s perceptions of change in terms of the limitations imposed on the patient’s daily activities (GEMS). Patient-reported HrQoL was measured by the SIP.
In general, efficacy variables were measured at baseline and at 3-monthly intervals until month 36 (end of treatment). Measures of HrQoL were performed at day 1 and at 6-monthly intervals for the trial duration.
Measurement of HrQoL.
SIP.
The SIP is a generic self-report questionnaire of HrQoL, which examines the individual’s perception of the impact of the disease process on behavior in everyday life.24 It is also referred to as the Functional Limitations Profile, which is simply the British version of the SIP.11,20⇓ The measure comprises 136 items grouped into 12 subscales; ambulation, mobility, body care and movement, social interaction, communication, alertness, emotional behavior, sleep and rest, eating, work, home management, and recreation and pastimes. Subscale scores are calculated by adding item scores, which have been weighted according to severity of limitation. From these subscales, two dimension scores (physical and psychosocial) can be calculated. The physical dimension is derived from the ambulation, mobility, and body care and movement scores; the psychosocial dimension is derived from the social interaction, communication, alertness, and emotional behavior scores. Likewise, a total score over the entire profile may be calculated.21 The score range is 0 to 100, where 0 is the best possible HrQoL and 100 is the worst. In this study, the patient completed the measure.
GEMS.
The GEMS scale was developed specifically for this study. It provides a global evaluation of the neurologist’s perception of change in terms of disease status and disability. The scale provides 7 points ranging from very much better to very much worse. The ratings are based on a range of sources including safety data (e.g., adverse events), neurologic impairment, disability, patient’s subjective state, and caregiver information. No published information is available determining its measurement properties.
Statistical methods.
Statistical analyses were based on the intention-to-treat population including all data of all patients as randomized without any restrictive criteria. HrQoL analyses included all data collected until the time of cutoff for interim analysis, which led to early termination of the study due to strong efficacy and based on a recommendation of an independent advisory board. Changes from baseline in total SIP score and physical and psychosocial dimension scores were evaluated at each time point. Nonparametric statistical methods were used,25 and p values from two-sided statistical tests were provided.
The QoL endpoints, change in total SIP score, and change in physical and psychosocial dimension score at an individual’s last visit were defined as tertiary endpoints in this study; that is, the focus was on differences between the groups in terms of changes over the whole study period. The p values were provided at each time but serve purely descriptive purposes.
Combined and individual SIP scale scores were compared between treatments using a nonparametric analysis of covariance with covariance adjustment for age, gender, education, and respective baseline score and stratification adjustment for countries. Goodman–Kruskal correlation coefficients were used to examine the relationship between the SIP scores and other variables.
Sample size was determined based on the primary efficacy endpoint as described previously2 and was not powered specifically to address HrQoL measures. All statistical analyses were performed by an independent institution using the SAS system (version 6.12, SAS, Cary, NC).
Results.
Baseline values.
The trial profile is illustrated in the figure. Overall, total SIP scores at baseline range from 1 to 48 (mean ± SD = 16.1 ± 8.8) for the placebo group and from 0 to 56 (mean ± SD = 15.9 ± 9.2) for the IFN group. When these results are stratified according to level of EDSS, they demonstrate that poorer levels of HrQoL are reported by patients with greater disease severity (where EDSS = 6.0, placebo mean ± SD SIP = 18.4 ± 8.4, IFN mean ± SD = 20.3 ± 9.8) compared with patients with lower levels of disease severity (where EDSS = 3.5, placebo mean ± SD SIP = 10.2 ± 6.6, IFN mean ± SD = 10.0 ± 5.9). In the main, this is also the case for each of the SIP subscale baseline scores (additional material related to this article can be found on the Neurology Web site; go to www.neurology.org and scroll down the Table of Contents to find the title link for this article). These subscale scores highlight difficulties with several aspects of the HrQoL, the areas most markedly affected being ambulation, home management, recreations, and pastimes.
Figure. Trial profile.
Difference between groups in SIP change scores over study period.
Complete data were not collected for all patients at every time point throughout but were most complete at 12 months and at exit from the study. Table 1 shows the changes from baseline to each assessment point for the total SIP scores and the physical and psychosocial dimension scores. The total scores demonstrate that for the first 18 months, the IFN group reported small but consistent improvements in HrQoL. From 24 months onward, a gradual deterioration becomes apparent. In contrast, the placebo group reported a gradual deterioration in their total scores from the first assessment onward. The differences between these two groups did not reach significance.
Baseline data and change from baseline for physical, psychosocial, and total SIP scores
The SIP physical dimension change scores demonstrate a slightly different pattern, with both groups reporting a steady deterioration in physical functioning from the first assessment onward. There is a consistent trend for a lessening of deterioration in the IFN group compared with the placebo group at every assessment point. Differences between the groups reach significance at 6 and 12 months and at last visit.
Finally, the psychosocial dimension scores show that both groups report small improvements in psychosocial aspects of HrQoL for the first 6 months. In the IFN group, this trend toward improvement continues until month 30, in contrast to the placebo group, where deterioration for the remainder of the study is reported. A significant treatment group difference was detected at month 18 but not at the last visit.
Confirmed progression by EDSS criteria.
Table 2 shows that the patients with confirmed progression on the EDSS (whether in the IFN or placebo group) report a deterioration in the SIP physical dimension scale scores by an average of 6 to 8 points (mean change = 7.6; 95% CI = 6.20, 9.00; effect size > 0.5). In contrast, patients without progression on the EDSS, regardless of group, show virtually no change on the SIP (mean change = −0.7; 95% CI = −1.71, 0.31). In the psychosocial dimension, patients from both groups who have confirmed progression show a small deterioration, although this is slightly less in the IFN group.
SIP physical and psychosocial dimension scores stratified for patients with/without confirmed progression*
Correlations between patient and physician assessment of change.
The association between patient-reported perception of change between baseline and end of treatment (determined by SIP physical and psychosocial dimension change scores) and the physician’s global evaluation of change (determined by the GEMS) was examined. The results were similar for both the IFN and the placebo groups; hence, the total group values are quoted. These demonstrate a moderate association between the SIP physical dimension change score and the GEMS change score (r = 0.44 to 0.52) but only a weak association between the SIP psychosocial dimension change score and the GEMS change score (r = 0.23 to 0.36).
Discussion.
Measuring the outcomes of therapeutic interventions from the patient’s perspective is important, as reflected by the increasing number of studies incorporating such measures within their evaluation. These include studies evaluating IFN-β therapy in MS,7,26-29⇓⇓⇓⇓ although methodologic issues limit interpretation of the results. We report the HrQoL data from a recent trial, which demonstrated the effectiveness of IFN-β1b in delaying EDSS progression in SP-MS.4 This was the first large, randomized, placebo-controlled clinical trial in MS to incorporate HrQoL data.
Our HrQoL results support the conclusions of the original study and show an overall trend for a slight lessening of deterioration in both the physical and the psychosocial dimensions of the SIP in the treatment group compared with the placebo group. Changes in the SIP physical domain occurred early in the study, in line with the positive changes documented for the biologic and MR data. The strength of this evidence is weak. First, significance was observed in only three of seven comparisons of the SIP physical summary score. Second, the magnitude of the change scores is small in comparison with the total scores, suggesting that any treatment effect is slight. Third, methods of interpreting changes in HrQoL are currently insufficiently developed to determine how clinically important these SIP score changes are for this population. There is, however, some evidence that the SIP may be less sensitive to improvement than to deterioration,30,31⇓ and although it is not known if this applies to MS, this should be considered when interpreting these results. Nevertheless, the direction of change in HrQoL supports the evidence that IFN-β1b prevents worsening and indicates a slight positive effect on HrQoL of the IFN group compared with the placebo group. Importantly, by assessing the patients’ perception of the impact of the disease on their everyday life, these HrQoL data provide an additional important perspective and widen the implications of the findings.
Construct validity for the SIP evidence is provided by the observation that, in general, patients deteriorating on the physician-assessed EDSS also report greater deterioration in the SIP physical dimension scores. Moreover, the neurologist’s global evaluation of change, measured by the GEMS, also correlates with changes on the SIP physical dimensions. This is consistent with the findings of others20 who found high correlations between clinical scales and the SIP.
Our data suggest that the EDSS and GEMS can address some aspects of physical function from the neurologist’s perspective. Physical disability, however, is just one factor that impacts on HrQoL in MS12,16,32⇓⇓; and neurologists’ and patients’ perceptions have been shown to differ.5 In line with other studies, these patients reported difficulties in a broad range of physical and psychosocial areas, with home management and recreations and pastimes most markedly affected. This underlines the need for trials to broaden the outcomes measured to include those relevant from the patient’s perspective.
Studies evaluating the impact of IFN therapies on HrQoL in MS have used a variety of different measures and have produced mixed results. One study, using the SF-36, found that IFNβ was associated with a small but significant improvement in physical role functioning over 6 months, although a transient worsening of bodily pain was noted.29 In contrast, another study, using the Q-twist measure, found that IFN-β1b did not significantly improve or detract from HrQoL after 12 months of treatment.26 IFN-α2A was also evaluated using the SF-36,6 with no benefit in HrQoL found at 6 months in spite of a marked effect on MRI. Indeed, a nonsignificant trend toward deterioration was seen in HrQoL for those treated with IFN-α2A compared with placebo. The use of different HrQoL measures makes comparison of these studies difficult, particularly since knowledge regarding the responsiveness of these measures is limited. It is therefore clear that, for this and other studies, we cannot be certain about the impact that this drug has on HrQoL; further studies are required, perhaps incorporating MS disease-specific measures that may be more sensitive.33 There is a need for some consensus on the optimal measures to determine this. This is especially important for comparing the relative effectiveness of different treatment regimens and evaluating the usefulness of information provided by disease-specific measures.
Acknowledgments
Supported Schering AG (Berlin).
Acknowledgment
The authors thank the patients who participated in this study.
Footnotes
-
The authors have received honoraria to lecture at conferences or participate at advisory meetings, but none of them holds any financial interest in the pharmaceutical company.
- Received July 21, 2000.
- Accepted July 27, 2001.
References
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