Daclizumab for relapsing remitting multiple sclerosis.

Cochrane Database of Systematic Reviews

Daclizumab for relapsing remitting multiple sclerosis (Review)

Liu J, Wang LN, Zhan S, Xia Y

Liu J, Wang LN, Zhan S, Xia Y. Daclizumab for relapsing remitting multiple sclerosis. Cochrane Database of Systematic Reviews 2013, Issue 12. Art. No.: CD008127. DOI: 10.1002/14651858.CD008127.pub4.

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Daclizumab for relapsing remitting multiple sclerosis (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . . . Figure 2. . . . . . . . . . . . . . . . . . . . . Figure 3. . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 Safety, Outcome 1 Any adverse event. . Analysis 1.2. Comparison 1 Safety, Outcome 2 Serious adverse event. APPENDICES . . . . . . . . . . . . . . . . . . . . WHAT’S NEW . . . . . . . . . . . . . . . . . . . . HISTORY . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . INDEX TERMS . . . . . . . . . . . . . . . . . . .

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[Intervention Review]

Daclizumab for relapsing remitting multiple sclerosis Jia Liu1 , Lu-Ning Wang1 , Siyan Zhan2 , Yinyin Xia3 1 Department of Geriatric Neurology, Chinese PLA General Hospital, Beijing, China. 2 Centre for Evidence Based Medicine and Clinical

Research, School of Public Health, Peking University, Beijing, China. 3 Dept. of Surveillance and Statistics, National Center for TB Control and Prevention, China CDC, Beijing, China Contact address: Jia Liu, Department of Geriatric Neurology, Chinese PLA General Hospital, Fuxing Road 28, Beijing, 100853, China. [email protected]. Editorial group: Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group. Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 12, 2013. Review content assessed as up-to-date: 12 July 2013. Citation: Liu J, Wang LN, Zhan S, Xia Y. Daclizumab for relapsing remitting multiple sclerosis. Cochrane Database of Systematic Reviews 2013, Issue 12. Art. No.: CD008127. DOI: 10.1002/14651858.CD008127.pub4. Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT Background Monoclonal antibodies such as daclizumab could be a possible alternative immunotherapy to interferon beta treatment in people with multiple sclerosis (MS). It blocks the interleukin-2 receptor alpha subunit (CD25), and seems to be beneficial to patients with relapsing remitting multiple sclerosis (RRMS) in clinical and magnetic resonance imaging (MRI) measures of outcomes. This is an update of a Cochrane review first published in 2010, and previously updated in 2012. Objectives To assess the safety of daclizumab and its efficacy to prevent clinical worsening in patients with RRMS. Search methods The Trials Search Co-ordinator searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register (17 May 2013). We handsearched the references quoted in the identified trials and reports (May 2013) from the most important neurological associations and MS societies. We contacted researchers participating in trials on daclizumab. Selection criteria All randomised controlled clinical trials (RCTs) evaluating daclizumab, alone or combined with other treatments versus placebo, or any other treatment for patients with RRMS. Data collection and analysis Two review authors independently assessed references retrieved for possible inclusion, extracted eligible data, cross-checked the data for accuracy and assessed the methodological quality. We resolved any disagreements by consensus among review authors. Main results We included two trials with 851 patients that evaluated the efficacy and safety of daclizumab versus placebo for RRMS. We judged them to be at low risk of bias. Due to different time point evaluations and available data on primary studies, we were unable to undertake a meta-analysis. At 24 weeks, the median change was 0 (range -2 to 3) in the interferon beta and placebo group, 0 (-2 to 4) in the interferon beta and low-dose daclizumab group and 0 (-2 to 2) in the interferon beta and high-dose daclizumab group in 230 Daclizumab for relapsing remitting multiple sclerosis (Review) Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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participants. The proportion of patients who had new clinical relapses were the following: 16 patients (21%) in the interferon beta and high-dose daclizumab group, 19 (24%) in the interferon beta and low-dose daclizumab group and 19 (25%) in the interferon beta and placebo group had relapses (P value = 0.87). At 52 weeks, the changes in Expanded Disability Status Scale (EDSS) from baseline was 0.09 ± 0.71 in placebo group, -0.08 ± 0.52 in low-dose daclizumab group and 0.05 ± 0.61 in high-dose daclizumab group in 621 participants. There was a significant difference between placebo and low-dose daclizumab groups (P value = 0.01), but no significant difference between placebo and high-dose daclizumab groups (P value = 0.49). The proportion of patients with new relapsing MS was significantly reduced in both daclizumab groups (19% in low-dose daclizumab group, 20% in high-dose daclizumab group) compared with placebo group (36%) (P value < 0.0001 and P value = 0.00032, respectively). There was no increased number of patients in any adverse events (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.89 to 1.07) or serious adverse events in daclizumab groups compared with placebo (RR 1.15, 95% CI 0.29 to 4.54). Infections were the most frequent adverse events in treated participants and were resolved with standard therapies. One trial was still ongoing. Authors’ conclusions There was insufficient evidence to determine whether daclizumab was more effective than placebo in patients affected by RRMS in terms of clinical and MRI measures of outcomes. Daclizumab appeared to be relatively well tolerated. Infections were the most frequent adverse events, and were resolved with standard therapies.

PLAIN LANGUAGE SUMMARY Daclizumab, an antibody, as possible alternative therapy to interferon beta in people with relapsing remitting multiple sclerosis Background Monoclonal antibodies such as daclizumab could be a possible alternative immunotherapy to interferon beta treatment in people with multiple sclerosis. This is an update of a Cochrane review first published in 2010, and previously updated in 2012. In this review, we aimed to evaluate the effectiveness and safety of daclizumab, alone or combined to other treatments for the improvement in relapsing remitting multiple sclerosis. Study characteristics To test the efficacy we measured the disability changes and the proportion of patients who had new relapses, while to test the safety we took into account the number of patients who exhibited any type of adverse events. We searched scientific databases for randomised controlled trials (clinical studies where people are randomly put into one of two or more treatment group) comparing daclizumab, alone or with other treatments versus placebo (a pretend treatment). Patients were aged 18 to 65 years with relapsing remitting multiple sclerosis. Evidence is current to May 2013. Key results We found two studies (funded by Facet Biotech/Biogen Idec and Biogen Idec/AbbVie Biotherapeutics Inc), which met our inclusion criteria, with 851 patients, both male and female, aged 18 to 65 years. The results did not provide sufficient evidence on the effectiveness of daclizumab, and further studies are needed. One study is still ongoing. Daclizumab was generally well-tolerated, the most frequent adverse events being infections, which were all resolved with standard therapies. In order to have more clear results, the length of followup (where the patients are observed and monitored following treatment) needs to be longer. Quality of the evidence We considered both studies to be of high quality.


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BACKGROUND

Description of the condition Multiple sclerosis (MS) is a neuroimmunological disease featured with demyelination in the central nervous system (CNS). MS can potentially cause all the neurological symptoms involving different CNS regions, such as visual loss, double vision, motor weakness, spasticity, ataxia, tremor, sensory loss, sphincter dysfunction and cognitive impairment (Compston 2002). Furthermore, relapses are the important features in MS, which can be triggered by numerous factors. A secondary progressive phase follows an exacerbating and remitting course in 80% of relapsing patients within two decades (Weinshenker 1989).

Why it is important to do this review Results of previous open-label studies of intravenous daclizumab in patients with active MS have suggested beneficial effects of daclizumab for both add-on and monotherapy protocols as measured by magnetic resonance imaging (MRI) and clinical outcomes (Bielekova 2009; Rose 2007). There were no severe safety concerns arising from clinical testing (Schippling 2008). However, no systematic review exists in the peer-reviewed literature that focuses on daclizumab for patients with relapsing remitting multiple sclerosis (RRMS). This is an update of a Cochrane review first published in 2010 (Liu 2010), and previously updated in 2012 (Liu 2012), to evaluate the efficacy and safety of daclizumab.

OBJECTIVES

Description of the intervention Based on new insights into the pathophysiology of MS, several novel selective immunotherapies are currently in clinical development. New monoclonal antibody treatments target specific cell populations, including B cells, T cells, immune cell migration into the brain and the inflammation associated with MS (Hemmer 2006). By selectively targeting individual cell populations rather than all of the immune system cells, these novel agents might provide improved safety profiles and enhanced efficacy. Daclizumab (Zenapax®), a humanised monoclonal antibody that blocks the interleukin-2 (IL-2) receptor alpha subunit (CD25), has been developed and is currently being investigated in the clinical treatment of MS. It is administered by subcutaneous or intravenous injections.

To assess the safety of daclizumab and its efficacy to prevent clinical worsening in patients with RRMS.

METHODS

Criteria for considering studies for this review

Types of studies All randomised controlled trials (RCTs) evaluating daclizumab, alone or combined with other treatments versus placebo, or any other treatment for patients with RRMS. We excluded uncontrolled, non-randomised or quasi-randomised trials. We considered both parallel group and cross-over design for inclusion.

How the intervention might work

Types of participants

IL-2 signalling plays a central role in the activation of immune responses, involving the accommodation of T cells, B cells and natural killer (NK) cells (Nelson 1998). Daclizumab inhibits Tcell expansion by binding to the CD25 epitope and masking the IL-2 binding site (Martin 2012), and dramatically reduces brain inflammation in patients with MS. Moreover, significant expansion of CD56 (bright) NK cells has been found in vivo by IL-2 receptor blockade, which is another possible mechanism of action through further inhibition of T-cell survival (Caligiuri 1993; Li 2005). It is used to prevent rejection in organ transplantation, especially in kidney transplants. The drug is currently under investigation for the treatment of MS. In the UK, the National Institute for Health and Care Excellence (NICE) has recommended that its be considered for all kidney transplant recipients (Webster 2010).

Inclusion criteria: • Males or females aged 18 to 65 years, inclusive. • Diagnosis of RRMS by the criteria of Poser (Poser 1983) for clinically definite or laboratory-supported definite MS or original or revised McDonald criteria (McDonald 2001; Polman 2005). • An Expanded Disability Status Scale (EDSS) score between 1.0 and 7.0. Exclusion criteria: • diagnosis of primary-progressive MS, pregnant or breastfeeding women, significant abnormality on electrocardiograph (ECG), malignancy, human immunodeficiency virus (HIV) infection, positive serology for hepatitis B virus (HBV) or hepatitis C virus (HCV), significant organ dysfunction.


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Types of interventions

Electronic searches

Experimental intervention: treatment with daclizumab intravenously or subcutaneously, alone or combined with other treatment. Control intervention: placebo or other treatments for MS.

The Review Group Trials Search Co-ordinator searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Trials Register (17 May 2013), which, among other sources, contains trials from: • The Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 2); • MEDLINE (PubMed) (1966 to 17 May 2013); • EMBASE (1974 to 17 May 2013); • CINAHL (EBSCOhost) (1981 to 17 May 2013); • LILACS (Bireme) (1982 to 17 May 2013); • PEDro (1990 to 17 May 2013) • Clinicaltrials.gov (www.clinicaltrials.gov); • World Health Organization (WHO) International Clinical Trials Registry Portal (apps.who.int/trialsearch/).

Types of outcome measures

Primary outcomes

We assessed the following primary outcomes measured at two years of follow-up.

Efficacy 1. Increased disability change defined as a six months’ sustained increase in EDSS of at least 1 to 2 points change (Kurtzke 1983). 2. Proportion of patients who had new clinical relapses.

Information on the Group’s Trials Register and details of search strategies used to identify trials can be found in the ’Specialised Register’ section within the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group’s module. The keywords used to search for this review are listed in Appendix 1. Searching other resources

Safety 1. Number of patients who exhibited any type of adverse events.

Secondary outcomes

We assessed the following secondary outcomes, measured in the treatment phase and at the completion of treatment versus baseline. 1. Number of new or enlarged gadolinium contrast-enhancing lesions (Gd-CELs) on monthly brain MRIs collected; 2. Number of total Gd-CELs on monthly brain MRIs collected; 3. Immunological biomarker measurement outcomes, which were measured in the treatment phase and at the completion of treatment versus baseline; 4. Mean change in Neurologic Rating Scale (NRS).

We handsearched the references quoted in the identified trials, the reports (January 2007 to May 2013) from the most important neurological associations and MS Societies (e.g. American Academy of Neurology, American Neurological Association, American Committee for Treatment and Research in MS, the European Committee for Treatment and Research in MS), and conference proceedings. Wecontacted the principle researchers of daclizumab trials and related pharmaceutical companies.

Data collection and analysis Selection of studies Two review authors (LJ, WL) independently screened titles and abstracts of the citations retrieved by the literature search to determine if the inclusion criteria were met, and obtained the full text of potentially relevant studies. We independently evaluated the eligibility (on the basis of information available in the published data), and assessed the methodological quality of the studies. We resolved any disagreements by discussion among review authors.

Search methods for identification of studies We conducted a systematic search without language restrictions to identify all relevant published and unpublished RCTs and crossover trials using the optimally sensitive strategy developed for The Cochrane Collaboration for the identification of RCTs (Lefebvre 2009).

Data extraction and management Two review authors (LJ,WL) independently extracted eligible data from the included studies onto standardised forms, and crosschecked them for accuracy. We resolved disagreements by consensus among the two review authors.


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We extracted the following data from each study: • methods of generating randomisation schedule; • method of concealment of allocation; • blinding of assessors; • use of an intention-to-treat analysis (all participants initially randomised were included in the analyses as allocated to groups); • adverse events and drop-outs for all reasons; • important imbalance in prognostic factors (onset of progression, relapse rate and disability in the initial five years); • participants (country, number of participants, type of MS, age, gender, EDSS score, inclusion and exclusion criteria); • comparison (details of the intervention in treatment and control groups; details of co-intervention(s) in both groups; duration of treatment); • outcomes and time points of measures (number of participants in each group and outcome, regardless of compliance). Assessment of risk of bias in included studies Two review authors (LJ, WL) independently assessed methodological quality of each included trial using the categories adequate sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting and other biases. We evaluated the quality of the included studies according to the criteria set out in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Furthermore, we assessed whether the treatment groups were comparable with regard to demographics, clinical characteristics and the number of patients excluded or lost to follow-up within each trial and whether the definition of outcomes and entry and exclusion criteria were comparable across the different trials. We only included cross-over studies if results from all periods and if the knowledge about number, allocation and period of loss to follow-up were available for analysis in order to estimate both the period and carry-over effects, and the bias introduced by imbalance of comparison groups. Measures of treatment effect We expected the RCTs and cross-over trials to measure both dichotomous data expressed as risk ratios (RR) with 95% confidence intervals (CIs) and continuous data expressed as mean differences (MD) with 95% CIs. Unit of analysis issues We dealt with unit of analysis issues according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

We considered using best- and worst-case scenarios for taking into account missing data. Assessment of heterogeneity We tested heterogeneity using the I2 statistic and made a judgement as to whether significant heterogeneity was present (Higgins 2011). We considered I2 values over 50% to be suggestive of substantial heterogeneity, and calculated the overall effects using a random-effects model instead of a fixed-effect model. Assessment of reporting biases We did not assess the reporting biases because of the limited number of studies included for data synthesis. In future updates and if more studies are included, potential publication bias will be examined using a funnel plot. For continuous outcomes, the standard errors will be used as the vertical axis and the MDs will be used as the horizontal axis in funnel plots. For dichotomous outcomes, the odds ratios or RRs will be plotted on a logarithmic scale as the horizontal axis and the standard errors will be used as the vertical axis. Data synthesis We carried out meta-analyses using the Review Manager 5 software routinely using a fixed-effect model (RevMan 2012). If we found statistically significant heterogeneity, we calculated the overall effects using a random-effects model instead of a fixed-effect model. If any heterogeneity between the studies prevented us from combining outcome data, we gave a descriptive summary of the results. Subgroup analysis and investigation of heterogeneity We did not perform subgroup analyses due to insufficient data. In future updates and if further data become available, we will analyse subgroups of studies categorised according to therapeutic approach, as outlined in the Types of interventions section. This includes a comparison of daclizumab alone or combined versus placebo treatment, and direct comparisons of daclizumab versus other pharmacological treatment. Sensitivity analysis We planned to undertake sensitivity analyses to assess the robustness of results to fixed-effect versus random-effects assumptions and the inclusion or exclusion of studies at high risk of bias. However, we did not performed analyses because of the low number of included studies and their low risk of bias.

Dealing with missing data We contacted the principal investigators to request missing information in the published trials and the data of unpublished trials.

RESULTS


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Description of studies Results of the search The search strategies retrieved 575 references. After screening of titles and abstracts, we obtained 12 full papers and assessed them for eligibility (Figure 1). We excluded 10 full-text articles and recorded the reasons for exclusion. We identified one ongoing RCT assessing the efficacy and safety of daclizumab versus interferon beta in patients with RRMS (NCT01064401).


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Figure 1. Study flow diagram.


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Included studies We included two studies involving 851 randomised patients in the review. Both were multicentre, double-blind, parallel RCTs. One study compared the efficacy of daclizumab (high/low doses), given subcutaneous versus placebo in 230 interferon beta-treated patients (Wynn 2010), while the other study evaluated the monotherapy of daclizumab (high/low-dose), in comparison with placebo in 621 patients (Gold 2013). Details of these trials are given in Characteristics of included studies table.

Excluded studies We excluded 10 studies for the following reasons: (1) not RCTs (Ali 2009; Bielekova 2004; Bielekova 2009; Bielekova 2011; Borges 2013; Rose 2004; Rose 2007; Yeh 2011); (2) case series without clinical outcomes reported (Bielekova 2006; Oh 2009). See Characteristics of excluded studies table.

Risk of bias in included studies The risk of bias summary are provided in Figure 2 and Figure 3.

Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included study.


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Figure 3. Risk of bias graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies.

Allocation

Selective reporting

Random assignments in both two studies were via centralised interactive voice response system, but unmasked to the site pharmacist who prepared the study drug. However, one study emphasised that the pharmacist had no interaction with the patients (Gold 2013), while the other study did not provide this information (Wynn 2010). Thus, we assessed low risk of bias and unclear risk of bias, respectively, in the two studies.

Both studies reported all specified primary and secondary outcomes.

Blinding

Effects of interventions

In both studies, all patients, medical monitors, clinical research associates, statisticians and bioanalysts were masked to treatment assignments by use of a blinded treatment code. They were assessed as low risk of bias.

Incomplete outcome data In Wynn 2010, overall 16 participants (total 7%, treated group 8% and placebo group 4%) discontinued treatment after randomisation with explicit reasons. In Gold 2013, 188 (92%) in placebo group, 192 (92%) in low-dose daclizumab group and 197 (94%) in high-dose daclizumab group completed follow-up to week 52. Thus, we assessed this as low risk of bias.

Other potential sources of bias We did not find any potential sources of bias. The studies were funded by Facet Biotech and Biogen Idec, and Biogen Idec and AbbVie Biotherapeutics Inc.

Efficacy We were unable to undertake a meta-analysis because the studies did not report the number of patients with sustained EDSS increase and the number of patients with relapses at 24 months. Thus, we have provided a descriptive summary of the results.

Changes in EDSS score

At 24 weeks, the median change was 0 (range -2 to 3) in the interferon beta and placebo group, 0 (-2 to 4) in the interferon beta and low-dose daclizumab group, and 0 (-2 to 2) in the interferon


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beta and high-dose daclizumab group in 230 participants (Wynn 2010). At 52 weeks, the mean changes in EDSS from baseline were 0.09 ± 0.71 in placebo group, -0.08 ± 0.52 in low-dose daclizumab group and 0.05 ± 0.61 in high-dose daclizumab group in 621 participants (Gold 2013). There was significant difference between placebo and low-dose daclizumab groups (P value = 0.01), but no significant difference between placebo and high-dose daclizumab groups (P value = 0.49).

Clinical relapse

At 24 weeks, the proportions of patients who had new clinical relapses were 19 (25%) in the interferon beta and placebo group, 16 (21% in the interferon beta and high-dose daclizumab group and 19 (24%) in the interferon beta and low-dose daclizumab group (P value = 0.87). The adjusted annualised relapse rate was 0.41 in the interferon beta and placebo group compared with 0.27 in the interferon beta and high-dose daclizumab group (difference 34%, 95% CI -44.38% to 70.10%; P value = 0.30) and 0.29 in the interferon beta and low-dose daclizumab group (difference 30%, 95% CCI -47.39% to 66.26%; P value = 0.35) (Wynn 2010). At 52 weeks, the annualised relapse rate was lower for patients in the low-dose daclizumab group (54% reduction, 95% CI 33% to 68%) or high-dose daclizumab group (50% reduction, 95% CI 28% to 65%) than for those given placebo. The proportion of patients with new relapses was significantly reduced in both daclizumab groups (19% in low-dose daclizumab group, 20% in high-dose daclizumab group) compared with placebo group (36%) (P value < 0.0001 and P value = 0.00032, respectively) (Gold 2013).

New or enlarged gadolinium contrast-enhancing lesions on brain magnetic resonance imaging

In Wynn 2010, the adjusted mean number of new or enlarged Gd-CELs was 4.75 in the interferon beta and placebo group compared with 1.32 in the interferon beta and high-dose daclizumab group (difference 72%, 95% CI 34% to 88%; P value = 0.004), and 3.58 in the interferon beta and low-dose daclizumab group (25% difference, 95% CI 68% to -76%; P value = 0.51). In Gold 2013, the mean number of new or enlarged Gd-CELs at week 52 was 1.4 ± 2.3 in placebo group, 0.3 ± 0.9 in low-dose daclizumab group and 0.2 ± 0.7 in high-dose daclizumab group. There were significant differences in both daclizumab groups compared with placebo group (P value < 0.0001). Meta-analysis was not performed because of the incompleteness of data and different time point of evaluation.

Immunologic biomarkers

In Wynn 2010, the number of CD56 (bright) NK cells was seven to eight times higher in the daclizumab groups than in the placebo group at week 20. In Gold 2013, CD56 (bright) NK cells in patients with daclizumab increased from a median of eight cells per microlitre (0.6% of lymphocytes) at baseline to 40 cells per microlitre (3.6% of lymphocytes) at the end of treatment. Increases in CD56 (bright) NK cells were significant at week four in both daclizumab groups versus placebo (P value < 0.0001).

DISCUSSION

Safety

Summary of main results

Both studies reported adverse events and serious adverse events. In the daclizumab and placebo groups, 459 of 570 (81%) patients and 236 of 281 (84%) patients, respectively, experienced any adverse events (RR 0.98, 95% CI 0.89 to 1.07) (Analysis 1.1), while 88 of 570 (15%) patients and 57 of 281 (20%) patients, respectively, experienced serious adverse events (RR 1.15, 95% CI 0.29 to 4.54) (Analysis 1.2). In Wynn 2010, the most frequent grade 3 adverse events were infections and infestations (10 of 153 (7%) in daclizumab groups vs. 2 of 77 (3%) in placebo group) (RR 2.52, 95% CI 0.57 to 11.20). No opportunistic infections or deaths were reported, and all infections resolved with standard therapies. In Gold 2013, there were nine (2%) patients with serious infections in daclizumab groups and no patients with serious infections in placebo group (RR 9.32, 95% CI 0.55 to 159.31). The numbers of patients with oral herpes infections (placebo 10 (5%), low-dose daclizumab 10 (5%), high-dose daclizumab 13 (6%)) were similar in all groups, as well as herpes zoster (one in each group).

This review aimed to evaluate the efficacy and safety of daclizumab in the treatment of clinical symptoms in RRMS. We found 575 references and included two studies with 851 participants that met our inclusion criteria. We were unable to undertake a meta-analysis because of lack of data and different time points of evaluation. Thus we reported only descriptive data on clinical and MRI measures of outcomes. For the change in EDSS score, the median change was 0 (range -2 to 3) in the interferon beta and placebo group, 0 (-2 to 4) in the interferon beta and low-dose daclizumab group, and 0 (-2 to 2) in the interferon beta and high-dose daclizumab group in 230 participants at 24 weeks (Wynn 2010). At 52 weeks, the changes in EDSS from baseline was 0.09 ± 0.71 in placebo group, -0.08 ± 0.52 in low-dose daclizumab group and 0.05 ± 0.61 in highdose daclizumab group in 621 participants. There was significant difference between placebo and low-dose daclizumab groups (P value = 0.01), but no significant difference between placebo and high-dose daclizumab groups (P value = 0.49) (Gold 2013).


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At 24 weeks, the proportion of patients who had new clinical relapses and the annualised relapse rate were not significantly different in the interferon and placebo group, in the interferon beta and high-dose daclizumab group, and in the interferon beta and low-dose daclizumab group (Wynn 2010). At 52 weeks, the annualised relapse rate was lower for patients in low-dose daclizumab (54% reduction, 95% CI 33% to 68%) or high-dose daclizumab (50% reduction, 95% CI 28% to 65%) than for those given placebo. The proportion of patients with new relapsing MS was significantly reduced in both daclizumab groups (19% in low-dose daclizumab group, 20% in high-dose daclizumab group) compared with placebo group (36%) (P value < 0.0001 and P value = 0.00032, respectively) (Gold 2013). With regards to safety, no change in number of patients with any adverse events (RR 0.98, 95% CI 0.89 to 1.07) or serious adverse events (RR 1.15, 95% CI 0.29 to 4.54) was found in daclizumab groups compared with placebo group. Infections were the most frequent adverse events and were resolved with standard therapies.

Overall completeness and applicability of evidence We included only two studies with 851 patients. Both studies reported efficacy as changes of EDSS score, clinical relapse, new or enlarged Gd-CELs on brain MRI and changes in volume of lesions on T1- and T2-weighted MRI. One study only found a significant difference in new or enlarged Gd-CELs, but not in the annualised relapse rate, changes in EDSS score or changes in volume of lesions on T1- and T2-weighted MRI (Wynn 2010). The other study demonstrated the significant differences in all outcomes (Gold 2013). These studies did not permit us to address the objectives of this review because of different outcome measures and time points of evaluation.

Potential biases in the review process None known.

Agreements and disagreements with other studies or reviews As far as we know, this is the first systematic review on this topic.

AUTHORS’ CONCLUSIONS Implications for practice There is insufficient evidence to determine whether daclizumab is more effective than placebo in patients affected by relapsing remitting multiple sclerosis (RRMS) both in terms of clinical and magnetic resonance imaging (MRI) measures of outcomes. The efficacy of daclizumab still needs to be further evaluated. Daclizumab appears to be relatively well tolerated. Infections were the most frequent adverse events, and were resolved with standard therapies.

Implications for research More research is required. In particular: 1. Length of treatment and follow-up needs to be longer. 2. Comparison should be better defined. In addition to placebo, other active controls should be considered to evaluate the efficacy and safetyof daclizumab.

Quality of the evidence

ACKNOWLEDGEMENTS

The quality of the evidence was limited by the low number of included studies and different time points of evaluation, although both of them were of high quality.

The authors would like to acknowledge the help provided by Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group.


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REFERENCES

References to studies included in this review Gold 2013 {published data only} ∗ Gold R, Giovannoni G, Selmaj K, Havrdova E, Montalban X, Radue EW, et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial. Lancet 2013;381:2167–75. Wynn 2010 {published data only} ∗ Wynn D, Kaufman M, Montalban X, Vollmer T, Simon J, Elkins J, et al. Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, doubleblind, placebo-controlled, add-on trial with interferon beta. Lancet Neurology 2010;9(4):381–90.

References to studies excluded from this review Ali 2009 {published data only} ∗ Ali EN, Healy BC, Stazzone LA, Brown BA, Weiner HL, Khoury SJ. Daclizumab in treatment of multiple sclerosis patients. Multiple Sclerosis 2009;15(2):272–4. Bielekova 2004 {published data only} ∗ Bielekova B, Richert N, Howard T, Blevins G, MarkovicPlese S, McCartin J, et al. Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon beta. Proceedings of the National Academy of Sciences of the United States of America 2004;101(23):8705–8. Bielekova 2006 {published data only} ∗ Bielekova B, Catalfamo M, Scrivner SR, Packer A, Cerna M, Waldmann TA, et al. Regulatory CD56(bright) natural killer cells mediate immunomodulatory effects of IL2Rα-targeted therapy (daclizumab) in multiple sclerosis. Proceedings of the National Academy of Sciences of the United States of America 2006;103(15):5941–6. Bielekova 2009 {published data only} ∗ Bielekova B, Howard T, Packer AN, Richert N, Blevins G, Ohayon J, et al. Effect of anti-CD25 antibody daclizumab in the inhibition of inflammation and stabilization of disease progression in multiple sclerosis. Archives of Neurology 2009;66(4):483–9. Bielekova 2011 {published data only} ∗ Bielekova B, Richert N, Herman ML, Ohayon J, Waldmann TA, McFarland H, et al. Intrathecal effects of daclizumab treatment of multiple sclerosis. Neurology 2011; 77(21):1877–86. Borges 2013 {published data only} ∗ Borges IT, Shea CD, Ohayon J, Jones BC, Stone RD, Ostuni J, et al. The effect of daclizumab on brain atrophy in relapsing-remitting multiple sclerosis. Multiple Sclerosis and Related Disorders 2013;2(2):133–40. Oh 2009 {published data only} ∗ Oh U, Blevins G, Griffith C, Richert N, Maric D, Lee CR, et al. Regulatory T cells are reduced during anti-

CD25 antibody treatment of multiple sclerosis. Archives of Neurology 2009;66(4):471–9. Rose 2004 {published data only} ∗ Rose JM, Watt HE, White AT, Carlson NG. Treatment of multiple sclerosis with an anti-interleukin-2 receptor monoclonal antibody. Annals of Neurology 2004;56(6): 864–7. Rose 2007 {published data only} ∗ Rose JW, Burns JB, Bjorklund J, Klein J, Watt HE, Carlson NG. Daclizumab phase II trial in relapsing and remitting multiple sclerosis: MRI and clinical results. Neurology 2007;69(8):785–9. Yeh 2011 {published data only} ∗ Yeh EA, Waubant E, Krupp LB, Ness J, Chitnis T, Kuntz N, et al. Multiple sclerosis therapies in pediatric patients with refractory multiple sclerosis. Archives of Neurology 2011;68(4):437–44.

References to ongoing studies NCT01064401 {unpublished data only} NCT01064401. Efficacy and safety of daclizumab high yield process versus interferon beta 1a in patients with relapsing remitting multiple sclerosis. www.clinicaltrials.gov/ct2/ show/NCT01064401 (accessed 11 December 2013).

Additional references Caligiuri 1993 Caligiuri MA, Murray C, Robertson MJ, Wang E, Cochran K, Cameron C, et al. Selective modulation of human natural killer cells in vivo after prolonged infusion of low dose recombinant interleukin 2. Journal of Clinical Investigation 1993;91(1):123–32. Compston 2002 Compston A, Coles A. Multiple sclerosis. Lancet 2002;359 (9313):1221–31. Hemmer 2006 Hemmer B, Nessler S, Zhou D, Kieseier B, Hartung HP. Immunopathogenesis and immunotherapy of multiple sclerosis. Nature Clinical Practice Neurology 2006;2(4): 201–11. Higgins 2011 Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Kurtzke 1983 Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33(11):1444–52. Lefebvre 2009 Lefebrvre C, Manheimer E, Glanville J. Chapter 6: Searching for studies. In: Higgins JPT, Green S


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(editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2 [updated September 2009]. The Cochrane Collaboration, 2009. Available from www.cochrane-handbook.org. Li 2005 Li Z, Lim WK, Mahesh SP, Liu B, Nussenblatt RB. Cutting edge: in vivo blockade of human IL-2 receptor induces expansion of CD56(bright) regulatory NK cells in patients with active uveitis. Journal of Immunology 2005;174(9): 5187–91. Martin 2012 Martin R. Anti-CD25 (daclizumab) monoclonal antibody therapy in relapsing-remitting multiple sclerosis. Clinical Immunology 2012;142(1):9–14. McDonald 2001 McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Annals of Neurology 2001;50(1):121–7. Nelson 1998 Nelson BH, Willerford DM. Biology of the interleukin-2 receptor. Advances in Immunology 1998;70:1–81. Polman 2005 Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the ’McDonald’ criteria. Annals of Neurology 2005;58(6):840–6. Poser 1983 Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Annals of Neurology 1983;13(3):227–31.

RevMan 2012 [Computer program] The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.2. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012. Schippling 2008 Schippling DS, Martin R. Spotlight on anti-CD25: daclizumab in MS. International MS Journal 2008;15(3): 94–8. Webster 2010 Webster AC, Ruster LP, McGee R, Matheson SL, Higgins GY, Willis NS, et al. Interleukin 2 receptor antagonists for kidney transplant recipients. Cochrane Database of Systematic Reviews 2010, Issue 1. [DOI: 10.1002/ 14651858.CD003897.pub3] Weinshenker 1989 Weinshenker BG, Bass B, Rice GP, Noseworthy J, Carriere W, Baskerville J, et al. The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain 1989;112(1):133–46.

References to other published versions of this review Liu 2010 Liu J, Wang L, Zhan S, Tan J, Xia Y. Daclizumab for relapsing remitting multiple sclerosis. Cochrane Database of Systematic Reviews 2010, Issue 6. [DOI: 10.1002/ 14651858.CD008127.pub2] Liu 2012 Liu J, Wang L, Zhan SY, Xia Y. Daclizumab for relapsing remitting multiple sclerosis. Cochrane Database of Systematic Reviews 2012, Issue 4. [DOI: 10.1002/ 14651858.CD008127.pub3] ∗ Indicates the major publication for the study


13

CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID] Gold 2013 Methods

Multicentre, randomised, double-blind, placebo-controlled, dose-ranging monotherapy study

Participants

Inclusion criteria: males or females aged 18-55 years, diagnosis of MS by McDonald criteria, EDSS ≤ 5.0 and had 1 confirmed MS relapse in the 12 months before randomisation 204 patients received placebo, 208 received daclizumab HYP 150 mg, 209 received daclizumab HYP 300 mg, with 188 (92%) people, 192 (92%), and 197 (94%), respectively, completing follow-up to week 52

Interventions

Subcutaneous injections of placebo, or daclizumab HYP 150 mg or 300 mg, every 4 weeks for 52 weeks

Outcomes

Primary outcomes: the annualised relapse rate at week 52. Secondary outcomes: clinical endpoints (proportion of relapsing patients at week 52, disability progression measured by change in EDSS score at week 52); MRI endpoints (new gadolinium-enhancing lesions between weeks 8 and 24 and at week 52; new or newly enlarging T2 hyperintense lesions at week 52; percentage change from baseline in volume T1- and T2-hyperintense lesions at week 52; percentage mean change in whole brain volume to week 24 and 52; quality-of-life endpoints (the changes measured by MSIS-29, EQ-visual analogue scale, EQ-5 Dimensions summary health index and SF12); adverse events

Notes

Study was carried out between 15 February 2008 and 14 May 2010

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Low risk bias)

Patients were randomly assigned in a 1:1:1 ratio.

Allocation concealment (selection bias)

Low risk

Assignment was via a centralised interactive voice response system, but unmasked to the site pharmacist who prepared the study drug for injection but had no interaction with the patient

Blinding of participants and personnel Low risk (performance bias) All outcomes

All personnel and patients were masked to treatment assignment


14

Gold 2013

(Continued)

Blinding of outcome assessment (detection Low risk bias) All outcomes

The members of an independent neurology assessment committee, consisting of MS neurologists, were masked to group assignment

Incomplete outcome data (attrition bias) All outcomes

Low risk

204 patients were assigned to receive placebo, 208 to daclizumab HYP 150 mg and 209 to daclizumab HYP 300 mg, of whom 188 (92%), 192 (92%), and 197 (94%), respectively, completed follow-up to week 52

Selective reporting (reporting bias)

Low risk

All pre-specified primary and secondary outcomes were reported

Other bias

Unclear risk

This study was funded by Biogen Idec and AbbVie Biotherapeutics Inc

Wynn 2010 Methods

Multicentre, randomised, double-blind, placebo-control, parallel assignment study

Participants

Inclusion criteria: males or females aged 18-55 years, diagnosis of MS by McDonald criteria, EDSS < 5.0, on stable interferon beta regimen for at least 6 months and had at least 1 MS relapse 288 patients were assessed for eligibility, and 230 were randomly assigned to receive interferon beta and high-dose subcutaneous daclizumab (n = 75), interferon beta and low-dose subcutaneous daclizumab (n = 78), or interferon beta and placebo (n = 77)

Interventions

High-dose was 2 mg/kg of subcutaneous daclizumab every 2 weeks for 11 doses. Lowdose was 1 mg/kg of subcutaneous daclizumab every 4 weeks for 6 doses alternating with placebo every 4 weeks for 5 doses. The control is subcutaneous placebo every 2 weeks for 11 doses

Outcomes

Primary outcomes: total number of new or enlarged gadolinium contrast-enhancing lesions on brain MRI scans done every 4 weeks between weeks 8 and 24 Secondary outcomes: changes in number and volume of lesions on T1- and T2-weighted MRI; clinical relapse as assessed by the annualised relapse rate and time to relapse; changes in EDSS and MSFC-3 scores; clinical laboratory abnormalities and adverse events

Notes

Study drug was given for 24 weeks. Then the participants were assessed for another 48 weeks for safety purposes

Risk of bias Bias

Authors’ judgement


Support for judgement

15

Wynn 2010

(Continued)

Random sequence generation (selection Low risk bias)

Randomisation was centralised and stratified by the dosing frequency of interferon beta (more than 2 vs. 1 dose per week) , EDSS score (0.0-2.0 vs. 2.5-5.0) and disease status (relapsing-remitting vs. secondary progressive)

Allocation concealment (selection bias)

The randomisation scheme was generated by Facet Biotech and sent to an interactive voice response system administrator. The patients’ treatment assignments were obtained by an unmasked study site pharmacist by telephone

Unclear risk

Blinding of participants and personnel Low risk (performance bias) All outcomes

All patients masked to treatment assignments by use of a blinded treatment code

Blinding of outcome assessment (detection Low risk bias) All outcomes

All medical monitors, clinical research associates, statisticians and bioanalysts masked to treatment assignments by use of a blinded treatment code

Incomplete outcome data (attrition bias) All outcomes

Low risk

Overall 16 participants (7%) discontinued after randomisation with explicit reasons

Selective reporting (reporting bias)

Low risk

All pre-specified primary and secondary outcomes were reported

Other bias

Unclear risk

This study was funded by Facet Biotech and Biogen Idec.

EDSS: Expanded Disability Status Scale; EQ: Euro Quality of Life; HYP: high-yield process; MRI: magnetic resonance imaging; MS: multiple sclerosis; MSFC-3: Multiple Sclerosis Functional Composite-3; MSIS: Multiple Sclerosis Impact Scale; SF-12: 12-item Short-Form Health Survey.

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Ali 2009

Case series: no control group.

Bielekova 2004



16

(Continued)

Bielekova 2006

Case series: no clinical outcomes reported.

Bielekova 2009


Bielekova 2011


Borges 2013

Retrospective analysis, not randomised controlled trial.

Oh 2009

Case series: no clinical outcomes reported.

Rose 2004


Rose 2007


Yeh 2011


Characteristics of ongoing studies [ordered by study ID] NCT01064401 Trial name or title

Multicenter, Double-blind, Randomized, Parallel-group, Monotherapy, Active-control Study to Determine the Efficacy and Safety of Daclizumab High Yield Process Versus Interferon beta 1a in Patients With RRMS

Methods

Treatment, randomised, double-blind, interferon beta 1a control, parallel assignment, safety/efficacy study

Participants

Males or females aged 18-55 years, with a confirmed diagnosis of RRMS, cranial MRI demonstrating lesions consistent with MS, and EDSS between 0.0 and 5.0 Sample size: 1800.

Interventions

Intervention: daclizumab 150 mg subcutaneous once every 4 weeks for 96-144 weeks Comparator: interferon beta 1a 30 µg intramuscular injection once weekly for 96-144 weeks

Outcomes

Primary outcome measures: preventing MS relapse in people with RRMS Secondary outcome measures: functional decline, disability progression and quality of life Time frame: visits from baseline visit and every 4 weeks thereafter for up to 144 weeks

Starting date

26 January 2010

Contact information

The information was provided by Biogen Idec.

Notes

Last updated: 16 August 2012

EDSS: Expanded Disability Status Scale; MS: multiple sclerosis; RRMS: relapsing remitting multiple sclerosis.


17

DATA AND ANALYSES

Comparison 1. Safety

Outcome or subgroup title

No. of studies

No. of participants

2 2

851 851

1 Any adverse event 2 Serious adverse event

Statistical method

Effect size

Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI)

0.98 [0.89, 1.07] 1.15 [0.29, 4.54]

Analysis 1.1. Comparison 1 Safety, Outcome 1 Any adverse event. Review:

Daclizumab for relapsing remitting multiple sclerosis

Comparison: 1 Safety Outcome: 1 Any adverse event

Study or subgroup

Daclizumab

Placebo

n/N

n/N

Gold 2013

310/417

161/204

40.8 %

0.94 [ 0.86, 1.03 ]

Wynn 2010

149/153

75/77

59.2 %

1.00 [ 0.96, 1.05 ]

570

281

100.0 %

0.98 [ 0.89, 1.07 ]

Total (95% CI)

Risk Ratio MH,Random,95% CI

Weight


Total events: 459 (Daclizumab), 236 (Placebo) Heterogeneity: Tau2 = 0.00; Chi2 = 3.30, df = 1 (P = 0.07); I2 =70% Test for overall effect: Z = 0.53 (P = 0.59) Test for subgroup differences: Not applicable

0.01

0.1

Favours [Daclizumab]

1

10

100

Favours [Placebo]


18

Analysis 1.2. Comparison 1 Safety, Outcome 2 Serious adverse event. Review:

Daclizumab for relapsing remitting multiple sclerosis

Comparison: 1 Safety Outcome: 2 Serious adverse event

Study or subgroup

Daclizumab

Placebo


Weight


n/N

n/N

Gold 2013

68/417

53/204

56.4 %

0.63 [ 0.46, 0.86 ]

Wynn 2010

20/153

4/77

43.6 %

2.52 [ 0.89, 7.11 ]

570

281

100.0 %

1.15 [ 0.29, 4.54 ]

Total (95% CI)

Total events: 88 (Daclizumab), 57 (Placebo) Heterogeneity: Tau2 = 0.84; Chi2 = 6.50, df = 1 (P = 0.01); I2 =85% Test for overall effect: Z = 0.20 (P = 0.84) Test for subgroup differences: Not applicable

0.01

0.1

Favours [Daclizumab]

1

10

100

Favours [Placebo]

APPENDICES Appendix 1. Keywords {daclizumab} OR {antigen} OR {zenapax} OR {dacliximab} OR {monoclonal antibody} OR {monoclonal antibodies} OR {antigens} AND {relapsing remitting} OR {relapsing-remitting} OR {remitting-relapsing} OR {remitting relapsing} OR {relapsing} OR {remitting} OR {relapsing AND remitting}

WHAT’S NEW Last assessed as up-to-date: 12 July 2013.

Date

Event

Description

12 July 2013

New citation required but conclusions have not changed Data from one study have been included in this update.

17 May 2013

New search has been performed

New search has been performed.


19

HISTORY Protocol first published: Issue 4, 2009 Review first published: Issue 6, 2010

Date

Event

Description

13 February 2012

New citation required and conclusions have changed

Data from one study have been included in this update (Wynn 2010).

10 February 2012

New search has been performed

New search has been performed.

CONTRIBUTIONS OF AUTHORS Liu J and Wang L formulated the idea and developed the basis for the review. Zhan S and Xia Y supervised the methodology and statistics. Liu J and Wang L were in charge of updating the review.

DECLARATIONS OF INTEREST None known.

SOURCES OF SUPPORT Internal sources • Department of Geriatric Neurology, Chinese PLA General Hospital, China.

External sources • No sources of support supplied

DIFFERENCES BETWEEN PROTOCOL AND REVIEW None.


20

INDEX TERMS Medical Subject Headings (MeSH) Antibodies, Monoclonal, Humanized [∗ therapeutic use]; Immunoglobulin G [∗ therapeutic use]; Immunosuppressive Agents [∗ therapeutic use]; Interferon-beta [therapeutic use]; Multiple Sclerosis, Relapsing-Remitting [∗ drug therapy]; Randomized Controlled Trials as Topic

MeSH check words Humans


21

Review of daclizumab and its therapeutic potential in the treatment of relapsing-remitting multiple sclerosis.

Dimethyl fumarate for relapsing-remitting multiple sclerosis.

Effect of daclizumab high-yield process in patients with highly active relapsing-remitting multiple sclerosis.

Bithalamic Inflammation in Relapsing-Remitting Multiple Sclerosis.

Current management of relapsing-remitting multiple sclerosis.

Alemtuzumab: a new therapy for active relapsing-remitting multiple sclerosis.

Interferons-beta versus glatiramer acetate for relapsing-remitting multiple sclerosis.

Teriflunomide for the treatment of relapsing-remitting multiple sclerosis.

Alemtuzumab for the treatment of relapsing-remitting multiple sclerosis.

Safety and efficacy of daclizumab in relapsing-remitting multiple sclerosis: 3-year results from the SELECTED open-label extension study.

Resting State Brain Entropy Alterations in Relapsing Remitting Multiple Sclerosis.

Fatigue predicts disease worsening in relapsing-remitting multiple sclerosis patients.

FADD is upregulated in relapsing remitting multiple sclerosis.

Interferon-beta and disability progression in relapsing-remitting multiple sclerosis.

Novel and imminently emerging treatments in relapsing-remitting multiple sclerosis.

Defective structural RNA processing in relapsing-remitting multiple sclerosis.

Established disease-modifying treatments in relapsing-remitting multiple sclerosis.

Effects of fingolimod in relapsing-remitting multiple sclerosis.

Growth factors and synaptic plasticity in relapsing-remitting multiple sclerosis.

Association of Immunotherapies With Outcomes in Relapsing-Remitting Multiple Sclerosis.

Teriflunomide in Patients with Relapsing-Remitting Forms of Multiple Sclerosis.

The efficacy of azathioprine in relapsing-remitting multiple sclerosis.

Autologous hematopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: comparison with secondary progressive multiple sclerosis.

Therapeutic efficacy of monthly subcutaneous injection of daclizumab in relapsing multiple sclerosis.