Rituximab for relapsing-remitting multiple sclerosis

  • Review
  • Intervention

Authors


Abstract

Background

This is an update of the Cochrane review "Rituximab for relapsing-remitting multiple sclerosis" (first published in The Cochrane Library 2011, Issue 12).

More than 80% of individuals with multiple sclerosis (MS) experience a relapsing-remitting disease course. Approximately 10 years after disease onset, an estimated 50% of individuals with relapsing-remitting MS (RRMS) convert to secondary progressive MS. MS causes a major socioeconomic burden for the individual patient and for society. Effective treatment that reduces relapse frequency and prevents progression could impact both costs and quality of life and help to reduce the socioeconomic burden of MS. Alternative and more effective MS treatments with new modes of action and good safety are needed to expand the current treatment repertoire. It has been shown that B lymphocytes are involved in the pathophysiology of MS and rituximab lyses B-cells via complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity. Current clinical trials are evaluating the role of rituximab as a B-cell depletion therapy in the treatment of RRMS.

Objectives

The safety and effectiveness of rituximab, as monotherapy or combination therapy, versus placebo or approved disease-modifying drugs (DMDs) (interferon-β (IFN-β), glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab) to reduce disease activity for people with RRMS were assessed.

Search methods

The Trials Search Co-ordinator searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register (9 August 2013). We checked the references in identified trials and manually searched the reports (2004 to August 2013) from neurological associations and MS societies in Europe and America. We also communicated with researchers who were participating in trials on rituximab and contacted Genentech, BiogenIdec and Roche.

Selection criteria

All randomised, double-blind, controlled parallel group clinical trials with a length of follow-up equal to or greater than one year evaluating rituximab, as monotherapy or combination therapy, versus placebo or approved DMDs for patients with RRMS without restrictions regarding dosage, administration frequency and duration of treatment.

Data collection and analysis

We used the standard methodological procedures of The Cochrane Collaboration. Two review authors independently assessed trial quality and extracted data. Disagreements were discussed and resolved by consensus among the review authors. Principal investigators of included studies were contacted for additional data or confirmation of data.

Main results

One trial involving 104 adult RRMS patients with an entry score ≤ 5.0 on the Expanded Disability Status Scale (EDSS) and at least one relapse during the preceding year was included. This trial evaluated rituximab as monotherapy versus placebo, with a single course of 1000 mg intravenous rituximab (on day 1 and day 15). A significant attrition bias was found at week 48 (24.0%). Patients receiving rituximab had a significant reduction in total number of gadolinium-enhancing lesions at week 24 (mean number 0.5 versus 5.5; relative reduction 91%) and in annualised rate of relapse at week 24 (0.37 versus 0.84) but not at week 48 (0.37 versus 0.72). Disability progression was not included as an outcome in this trial. More patients in the rituximab group had adverse events within the 24 hours after the first infusion (78.3% versus 40.0%), such as chills, headache, nausea, pyrexia, pruritus, fatigue, throat irritation, pharyngolaryngeal pain, and most were mild-to-moderate events (92.6%). The most common infection-associated adverse events (> 10% in the rituximab group) were nasopharyngitis, upper respiratory tract infections, urinary tract infections and sinusitis. Among them, only urinary tract infections (14.5% versus 8.6%) and sinusitis (13.0% versus 8.6%) were more common in the rituximab group. One ongoing trial was identified.

Authors' conclusions

There is not sufficient evidence to support the use of rituximab as a disease-modifying therapy for RRMS because only one RCT was included. The quality of the study was limited due to high attrition bias, the small number of participants, and short follow-up. The beneficial effects of rituximab for RRMS remain inconclusive. However, short-term treatment with a single course of rituximab was safe for most patients with RRMS. Mild-to-moderate infusion-associated adverse events were common, as well as nasopharyngitis, upper respiratory tract infections, urinary tract infections and sinusitis. The potential benefits of rituximab for treating RRMS need to be evaluated in large-scale studies that are of high quality along with long-term safety.

Plain language summary

The use of the monoclonal antibody rituximab in patients with relapsing remitting multiple sclerosis (RRMS)

This is an update of the Cochrane review "Rituximab for relapsing-remitting multiple sclerosis" (first published in The Cochrane Library 2011, Issue 12).

Recent studies showed that a class of white blood cells (B lymphocytes) can be involved in the pathology of MS. This feature has led to a renewed interest in therapies directed at controlling B-cell activity. Rituximab belongs to the class of monoclonal antibodies and is able to diminish the number of B lymphocytes in the cerebrospinal fluid. The authors of this review assessed the efficacy and safety of rituximab in patients with RRMS, taking into account relapses, brain lesions and disease progression. From the pertinent literature, only one study evaluating rituximab versus placebo in 104 adult patients with at least one relapse during the preceding year was included.

The authors did not find convincing evidence to support rituximab as an effective treatment for RRMS, also because the quality of the one identified study was limited due to high attrition bias, the small number of participants, and short follow-up. As far as safety is concerned, patients reported infusion-associated adverse events within the 24 hours after the first infusion, including chills, headache, nausea, pyrexia, pruritus, fatigue, throat irritation and pharyngolaryngeal pain. Among infection-associated adverse events, only urinary tract infections (in 14.5% versus 8.6%) and sinusitis (13.0% versus 8.6%) were more common in the rituximab group. The potential benefits of rituximab for treating RRMS need to be further evaluated in large-scale studies that are of high quality along with long-term safety.

Summary of findings(Explanation)

Summary of findings for the main comparison. Rituximab for relapsing-remitting multiple sclerosis
  1. 1 This study had a high rate of dropouts (24.0%), and the methodology for random sequence generation and allocation concealment was unclear.
    2 This study had a small sample size and would only have 70% power for the primary endpoint.

Rituximab for relapsing-remitting multiple sclerosis
Patient or population: patients with relapsing-remitting multiple sclerosis
Settings: this trial was performed in the United States and Canada
Intervention: rituximab
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control Rituximab
The annualised rate of relapse
Scale from: 0 to infinity.
Follow-up: mean 48 weeks
The mean the annualised rate of relapse in the control groups was
0.72
The mean the annualised rate of relapse in the intervention groups was 0.35 lower
(0.75 to 0.05 lower)
 104
(1 study)
⊕⊕⊝⊝
low 1,2
 
The sum of the number of gadolinium-enhancing T1-weighted lesions
Scale from: 0 to infinity.
Follow-up: mean 24 weeks
The mean the sum of the number of gadolinium-enhancing t1-weighted lesions in the control groups was
5.5
The mean the sum of the number of gadolinium-enhancing t1-weighted lesions in the intervention groups was
5 lower
(0.75 to 0.01 lower)
 104
(1 study)
⊕⊕⊝⊝
low 1,2
 
The number of patients with adverse effects
Follow-up: mean 48 weeks
High RR 0.99
(0.94 to 1.05)
104
(1 study)
⊕⊕⊝⊝
low 1,2
 
100 per 100 99 per 100
(94 to 100)
The number of patients with serious adverse events
Follow-up: mean 48 weeks
Low RR 0.91
(0.33 to 2.52)
104
(1 study)
⊕⊕⊝⊝
low 1,2
 
143 per 1000 130 per 1000
(47 to 360)
The number of patients who withdrew or dropped out from the study because of AEs
Follow-up: mean 48 weeks
Low RR 0.76
(0.13 to 4.35)
104
(1 study)
⊕⊕⊝⊝
low 1,2
 
57 per 1000 43 per 1000
(7 to 248)
The number of patients with disability progression Study populationNot estimable0
(0)
See commentThis outcome was not included as an endpoint in the trial.
See commentSee comment
 
  
The time to confirmed disease progression Study populationNot estimable0
(0)
See commentThis outcome was not included as an endpoint in the trial.
See commentSee comment
 
  
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system (CNS) in which autoreactive CD4+ and CD8+ T lymphocytes, B lymphocytes, antibodies, macrophages and cytokines synergize in myelin sheath attack and injury of the underlying axons. It is characterized by recurrent relapses and / or progression that are attributable to multifocal inflammation, demyelination and axonal loss within the CNS, typically striking adults during the primary productive time of their lives and ultimately leading to severe neurological disability.

Initially, more than 80% of individuals with MS experience a relapsing-remitting disease course (RRMS) characterized by clinical exacerbations of neurologic symptoms followed by complete or incomplete remission (Lublin 1996). After 10 to 20 years, or median age of 39.1 years, about half gradually accumulate irreversible neurologic deficits with or without clinical relapses (Confavreux 2006), which is known as secondary progressive MS (SPMS).

MS causes a major socioeconomic burden for the individual patient and for society. Increasing costs and decreasing quality of life are associated with advancing disease severity, disease progression and existence of relapses (Karampampa 2012a). From a patient's perspective an MS relapse is associated with a significant increase in the economic costs as well as a decline in health related quality of life and functional ability (Oleen-Burkey 2012).

Effective treatment that reduces relapse frequency and prevents progression could impact both costs and quality of life and may help to reduce the social burden of MS (Karampampa 2012b). On the basis of high quality evidence, natalizumab and interferon β-1a (IFNβ-1a) (Rebif) are superior to mitoxantrone, glatiramer acetate, IFNβ-1b (Betaseron), IFNβ-1a (Avonex), methotrexate, cyclophosphamide, azathioprine, intravenous immunoglobulins and long-term corticosteroids for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. However they are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable (Filippini 2013). Therefore, alternative MS treatments with new modes of action and good safety are needed to expand the current treatment repertoire, such as B-cell directed therapy.

Description of the intervention

Evidence is accumulating on the involvement of B lymphocytes in the pathophysiology of MS. The contribution of B-cells and their secreted products to MS may relate to the abilities of B-cells to (1) differentiate into plasmocytes that produce antibodies; (2) function as antigen-presenting cells, contributing to T-cell activation; (3) produce effector cytokines that may modulate the local immune environment; (4) harbour the Epstein-Barr virus in a chronically activated state; and (5) play a role in the formation and maintenance of new lymphoid foci within the CNS (Waubant 2008). In people with RRMS, B-cells are critical for T-cell trafficking into the CNS and may alter the process by influencing chemokine production within the CNS (Piccio 2010). Interleukin-6 (IL-6) secretion is a major mechanism of B-cell driven pathogenesis in experimental autoimmune encephalomyelitis (EAE) and MS (Barr 2012). B-cell depletion affects antibody production, cytokine networks, and B-cell mediated antigen presentation and activation of T-cells and macrophages in MS (Duddy 2006).

Rituximab is a glycosylated immunoglobulin G1 (IgG1) κ chimeric mouse-human antibody that binds to the CD20 antigen present on the majority of circulating B-cells, with the exception of plasma cells and haematopoietic stem cells (Waubant 2008). Rituximab lyses circulating B-cell populations via complement-dependent cytotoxicity (CDC) (Di Gaetano 2003), antibody-dependent cellular cytotoxicity (ADCC), and possibly promotion of apoptosis (Reff 1994). It is indicated for the treatment of patients with non-Hodgkin's lymphoma (375 mg/m2, intravenously); chronic lymphocytic leukaemia (375 mg/m2 in the first cycle and 500 mg/m2 in cycles 2 to 6, intravenously); rheumatoid arthritis (RA) in combination with methotrexate in adult patients with moderate to severe active RA who have an inadequate response to one or more tumour necrosis factor antagonist therapies (two intravenous infusions of a fixed dosage of 1000 mg separated by 2 weeks (one course) every 24 weeks); granulomatosis with polyangiitis (Wegener's granulomatosis) and microscopic polyangiitis in adult patients in combination with glucocorticoids (375 mg/m2 once weekly for 4 weeks, intravenously) (FDA 2013).

The application of rituximab to the treatment of MS uses intravenous administration of a fixed dosage of 1000 mg rituximab on day 1 and 15 (one course), with subsequent courses of treatment at week 24 (day 169), week 48 (day 337) and week 72 (day 505) and a second infusion 14 ± 1 days after the first one (Taupin 2011). This scheme has been adopted in recent RRMS trials. After two courses of intravenous rituximab infusion, serum drug concentrations exhibit a biphasic profile and the mean terminal half-life of the drug is 22 days. B-cell depletion has been shown to be near complete (99.8%) by week two and sustained through week 48 (Bar-Or 2008). The treatment with rituximab also causes a depletion of cerebrospinal fluid (CSF) B-cells 24 weeks after the initial treatment in MS patients in association with a reduction in CSF T-cells (Cross 2006). B lymphocytes were depleted from brain tissue after rituximab therapy in patients with MS (Martin 2009). B-cell depletion therapy (BCDT) with rituximab normalized the elevated levels of IL-6 as a result of secretion by B-cells in RRMS patients (Barr 2012). Current clinical trials are evaluating a role for B-cell depletion therapy using rituximab in the treatment of MS.

How the intervention might work

Preliminary results of an open-label study using two courses of intravenous rituximab in people with RRMS suggested that rituximab reduced new gadolinium-enhancing or T2 lesions and relapses without serious adverse events (Bar-Or 2008). Very recently, results of a study of rituximab add-on therapy (375 mg/m2 intravenously at weekly intervals, 4 doses) in patients with RRMS demonstrate that rituximab (added on to INFβ-1a, INFβ-1b or glatiramer acetate) reduced gadolinium-enhancing brain lesions (Naismith 2010). In a randomised, double-blind, placebo-controlled, multicentre study with a single course of rituximab in people with RRMS, rituximab (monotherapy versus placebo) demonstrated efficacy in reducing disease activity (relapses and gadolinium-enhancing lesions) by selectively depleting CD20+ B-cells (Hauser 2008).

Why it is important to do this review

Although trials on the use of rituximab for relapsing and progressive MS have been systematically reviewed (Castillo-Trivino 2013), a systematic review of all randomised controlled trials is warranted to evaluate the effectiveness and safety of rituximab for RRMS.

This is an update of the Cochrane review "Rituximab for relapsing-remitting multiple sclerosis" (first published in The Cochrane Library 2011, Issue 12).

Objectives

The safety and effectiveness of rituximab, as monotherapy or combination therapy, versus placebo or approved disease-modifying drugs (DMDs) (IFN-β, glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab) to reduce disease activity for people with RRMS were assessed.

Methods

Criteria for considering studies for this review

Types of studies

All randomised, double-blind, controlled parallel group clinical trials evaluating rituximab, as monotherapy or combination therapy, versus placebo or approved DMDs for people with RRMS. Uncontrolled, non-randomised or quasi-randomised trials were excluded. Trials with a length of follow-up shorter than one year were excluded.

Types of participants

Inclusion criteria

(1) Definite diagnosis of MS according to Poser's (Poser 1983) or McDonald's (McDonald 2001; Polman 2005; Polman 2011) criteria

(2) Male or female, any race, aged > 18 years

(3) Expanded Disability Status Scale (EDSS) (Kurtzke 1983) scores ≤ 6.0

(4) Clinical course characterised by a relapsing-remitting disease course

(5) Irrespective of duration of disease, frequency of relapse

Exclusion criteria

Diagnosis of other types of MS, such as secondary progressive, primary progressive, or progressive relapsing MS

Types of interventions

Experimental intervention

Treatment with intravenous rituximab, as monotherapy or combination therapy, without restrictions regarding dosage, administration frequency and duration of treatment

Control intervention

Placebo or an approved DMDs

Types of outcome measures

Primary outcomes

We assessed the following primary outcomes measured in the treatment phase and at the completion of follow-up versus baseline.

Efficacy

(1) The annualised rate of relapse at one year (or later), defined as the mean number of confirmed relapses per patient adjusted for the duration of follow-up to annualise it. Relapse is defined as the occurrence of new symptoms or worsening of previously stable or improving symptoms and signs that are not associated with fever or infection, occurring at least 30 days after the onset of a preceding relapse and lasting more than 24 hours.

(2) The sum of the number of gadolinium-enhancing T1-weighted lesions at one year (or later). Lesions that persisted for more than four weeks were counted more than once.

Safety

The number of patients with adverse effects (AEs), number of patients with serious adverse events (SAEs), and number of patients who withdrew or dropped out from the study because of AEs measured at one year (or later).

Secondary outcomes

We assessed the following secondary outcomes, measured in the treatment phase and at the completion of follow-up versus baseline.

(1) The number of patients with disability progression at two years (or later). We accepted the definitions of confirmed disability progression reported in the included trials.

(2) The time to confirmed disease progression at two years (or later).

(3) Mean change in quality of life (QoL). The following scales were accepted: Short Form-36 (SF-36) (Ware 1992), Multiple Sclerosis Quality of Life-54 (MSQOL-54) (Vickrey 1995), Multiple Sclerosis Quality of Life Inventory (MSQLI) (Fischer 1999), or Functional Assessment of MS (FAMS) (Cella 1996) at two years (or later).

Search methods for identification of studies

No language restrictions were applied to the search.

Electronic searches

The Review Group Trials Search Co-ordinator searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Trials Register (9 August 2013) which, among other sources, contains trials from:

  1. Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 3);

  2. MEDLINE (PubMed) (1966 to 9 August 2013);

  3. EMBASE (Embase.com) (1974 to 9 August 2013);

  4. CINAHL (EBSCOhost) (1981 to 9 August 2013);

  5. LILACS (Bireme) (1982 to 9 August 2013);

  6. PEDro (1990 to 9 August 2013);

  7. Clinicaltrials.gov (www.clinicaltrials.gov);

  8. World Health Organization (WHO) International Clinical Trials Registry Portal (http://apps.who.int/trialsearch/).

Information on the Cochrane Multiple Sclerosis Group Trials Register and details of the 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 module.

The keywords used to search for this review are listed in Appendix 1.

Searching other resources

  1. We checked references cited in identified trials

  2. We handsearched reports (2004 to August 2013) from neurological associations and MS Societies in Europe and America (The Society for Neuroscience, The American Academy of Neurology, The World Federation of Neurology, Federation of European Neuroscience Societies, British Neuroscience Association, National Multiple Sclerosis Society)

  3. We communicated with researchers participating in trials on rituximab

  4. We contacted Genentech (http://www.gene.com/gene/index.jsp); BiogenIdec (http://www.biogenidec.com); Roche (http://www.roche.com/index.htm) in an effort to identify further studies

Data collection and analysis

Selection of studies

Titles and abstracts of the references identified by the literature search were screened independently for inclusion or exclusion by two review authors (He and Dong). The full texts of potentially relevant studies were selected for further assessment. The eligibility of these studies was evaluated independently. Papers that did not meet the inclusion criteria were listed in the 'Characteristics of excluded studies' table with the reason for omission. Disagreement regarding inclusion was resolved by discussion or by referral to a third assessor (Zhou), if necessary.

Data extraction and management

Two review authors (He and Dong) independently extracted data from the selected trials using standardised forms. Information about study design, participants, the intervention and outcome measures were extracted. Principal investigators of included studies were contacted so that they could provide additional data or confirmation of methodological aspects of the study. Disagreements were discussed and resolved by consensus among the review authors.

Assessment of risk of bias in included studies

The methodological criteria were based on the Cochrane Handbook for Systematic Reviews of Interventions, version 5.1.0 (Higgins 2011). Two review authors (He and Dong) independently evaluated the methodological quality of the studies using the risk of bias tool under the domains of random sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other biases. Studies with a high risk of bias were excluded. Disagreements among the review authors on the methodological quality of the identified studies were discussed and resolved by consensus.

Measures of treatment effect

We did not enter any data into the RevMan analysis because only one study was included in this review. If data are available in future updates we will analyse them as follows.

The pre-set outcomes in this review involved counts and rates, dichotomous, ordinal (measurement scales) and time-to-event data.

Both the number of relapses and new enhancing lesions are count data. Analyses of counts of rare events (Poisson data) often focus on rates (rates relate the counts to the amount of time during which they could have happened). Rate ratio, which compares the rate of events in the two groups by dividing one by the other, will be used to measure the treatment effect on counts of rare events. When measuring the treatment effect on counts of common events, the mean difference will be used to compare the difference in the mean number of events (possibly standardised to a unit time period) experienced by the participants in the intervention group compared with the participants in the control group. Both MS relapse and gadolinium-enhancing T1-weighted lesions are common events, therefore the mean difference will be used as the measure of treatment effect.

For dichotomous outcomes, individual and pooled statistics will be calculated as relative ratio (RR) or odds ratio (OR), the risk difference (RD) (also called the absolute risk reduction) and the number needed to treat (NNT). Both the number of patients with disability progression and the number of patients with adverse effects are dichotomous outcomes, and we will use RRs as the measure of treatment effect.

Where the ordinal rating scales used in the trials have a reasonably large number of categories, the data will be treated as continuous outcomes arising from a normal distribution. Mean change in QoL is ordinal data. For trials that have used the same rating scale to assess outcome the mean difference will be used as the measure of treatment effect. Where different rating scales have been used the measure of the treatment difference is the standardised mean difference.

Time-to-event data can be analysed as dichotomous data when the status of all patients in a study is known at a fixed time point. The time to confirmed disability progression provides time-to-event data; we will use RRs or hazard ratios as the measure of treatment effect.

For continuous variables, mean values before and after the intervention, the mean change from baseline, standard deviations, and the number of patients for each treatment group of the individual studies will be extracted. The standard deviation will be calculated from the confidence interval or t-tests when not reported. The standard error of the mean change will be calculated from the standard deviation. For binary outcomes, the number of patients for each treatment group of the individual studies and the number of patients incurring the event in each group will be extracted.

Unit of analysis issues

The pre-set outcome measures in this review involve events that may reoccur. If data are available in future updates, for the trials with multiple arms we will combine all relevant experimental intervention groups in the study into a single group and combine all relevant control intervention groups into a single control group if there is a study with two control intervention groups treated with the same drug and different doses. Meanwhile, we will perform separate analyses based on the pre-set outcomes in this review and the different periods of follow-up.

Dealing with missing data

We did not conduct a meta-analysis, so trial authors were not contacted for missing data. If sufficient data are not available from published reports in future updates, the authors will be contacted for further details. A last observation carried forward imputation strategy will be used for data not missing at random and the intention-to-treat principle will be used for the analyses. For the data assumed to be missing at random, only the available data will be analysed. We will address the potential impact of missing data on the findings of the review in the 'Discussion' section.

Assessment of heterogeneity

The one study included in this review did not permit an assessment of heterogeneity. If more studies are included and further data become available in future updates, we will assess clinical heterogeneity by examining the characteristics of the studies, the similarity between the types of participants, the interventions and the outcomes as specified in the criteria for included studies. The variability in study design and risk of bias (methodological heterogeneity) will be also evaluated. When pooling trials in meta-analyses, the I2 statistic will be calculated to identify heterogeneity across studies. With I2 > 30% there is some level of heterogeneity (Higgins 2011). If tests for heterogeneity are statistically significant and inspection of the individual results suggests that it still logical to combine results, we will calculate the overall effects using a random-effects model.

Assessment of reporting biases

We could not perform an assessment of reporting biases due to the lack of adequate studies included in this review. If sufficient RCTs are identified in future updates, potential publication bias will be examined using a funnel plot. For continuous outcomes, the standard error will be used as the vertical axis and the mean difference will be used as the horizontal axis in funnel plots. For dichotomous outcomes, the odds ratio or risk ratio will be plotted on a logarithmic scale as the horizontal axis and the standard error will be used as the vertical axis.

Data synthesis

We were unable to conduct meta-analysis because only one study was included in this review. We have given a descriptive summary of the results. When clinically and methodologically homogeneous randomised controlled trials (RCTs) are identified in future updates and heterogeneity tests suggest an I2 < 30%, or inspection of the individual results suggests that it still seems logical to combine results even though tests for heterogeneity are statistically significant, formal meta-analysis will be conducted using Review Manager software (Review Manager 2013). Treatment effect estimates for each study and the weighted average of the treatment effects estimated in the individual studies (as a pooled treatment effect estimate) will be calculated, then a random-effects model or fixed-effect model will be selected according to the results of the heterogeneity tests. If it is assumed that each study is estimating exactly the same quantity a fixed-effect model will be performed, otherwise a random-effects model will be used. For the outcomes treated as dichotomous data (the number of patients with disability progression, the number of patients with adverse effects, and the time to confirmed disability progression), three fixed-effect model methods (Mantel-Haenszel, Peto, or inverse variance) and one random-effects model method (DerSimonian and Laird) will be selected (the Peto method can only pool odds ratios whilst the other three methods can pool odds ratios, risk ratios, and risk differences). For the outcomes treated as continuous and count data (relapse, the number of gadolinium-enhancing T1-weighted lesions, mean change in QoL), the inverse-variance fixed-effect model method and the inverse-variance random-effects model method will selected.

Subgroup analysis and investigation of heterogeneity

The lack of data did not permit a subgroup analysis, but in future updates and if further data become available we intend to undertake subgroup analyses according to: (1) different therapies (monotherapy, combination therapy); (2) duration of follow-up (1 year, between 1 and 2 years, more than 2 years); (3) baseline EDSS scores (≤ 3.5, between 3.5 and 6); (4) dosage level (recommended dosage in MS as a fixed dosage of 1000 mg (intravenous), given as a repeated course on day 1 and 15 every 24 weeks with second infusion 14 ± 1 days after the first one, other dosage including 375 mg/m2 given intravenously weekly for 4 doses).

Sensitivity analysis

If a sufficient number of studies had been included, we would have undertaken sensitivity analyses to assess the robustness of our review results. Where possible, we will conduct sensitivity analyses to assess the influence on results of fixed-effect model versus random-effects model assumptions, of including trials at high risk of bias, analysing the results by intention to treat, and the effect size (for dichotomous outcomes relative ratios versus odds ratios; and for continuous outcomes the mean difference versus the standardised mean difference).

Results

Description of studies

See: 'Characteristics of included studies', 'Characteristics of excluded studies' and 'Characteristics of ongoing studies'.

Results of the search

A total of 431 articles were retrieved by the search strategy. After screening of titles and abstracts, three articles were provisionally selected. The full papers were obtained for further assessment of eligibility. We excluded two studies: one study (Bar-Or 2008) was an open-label trial; one (Naismith 2010) was an uncontrolled trial. Only one study met the inclusion criteria (Hauser 2008). One study is ongoing (NCT01569451). See Figure 1.

Figure 1.

Study flow diagram.

Included studies

One study was included. The Hauser 2008 study evaluated the efficacy and safety of rituximab as monotherapy versus placebo for adults with RRMS (n = 104) (Characteristics of included studies). All participants were aged 18 to 55 years and had a diagnosis of RRMS (McDonald 2001), an entry score of 0 to 5.0 on the EDSS, and at least one relapse during the preceding year but without a relapse within 30 days. Patients received intravenous infusions of 1000 mg rituximab (n = 69) or placebo (n = 35) on study days 1 and 15; 30 to 60 minutes before each infusion acetaminophen (at a dose of 1 g) and diphenhydramine hydrochloride (at a dose of 50 mg) were administered orally as premedication. This trial was supported by Biogen Idec and Genentech.

Excluded studies

Two studies were excluded from this review. Reasons for their exclusion are available in the Characteristics of excluded studies table.

Risk of bias in included studies

Further details of this assessment are available in the relevant section of the Characteristics of included studies table and are also presented in the 'Risk of bias' graph (Figure 2) and 'Risk of bias' summary (Figure 3).

Figure 2.

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

Figure 3.

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

Allocation

The specific methods of random sequence generation and allocation concealment were not mentioned. We wrote to the principal author but we did not receive a reply. The risk of selection bias was unclear.

Blinding

This trial was double-blinded. The risks of performance bias and detection bias were low.

Incomplete outcome data

A high rate of dropouts (24%) over a period of 48 weeks occurred. The reasons for discontinuation were not balanced between the groups. The risk of attrition bias was high.

Selective reporting

All listed outcomes were reported adequately in the study. The risk of reporting bias was low.

Other potential sources of bias

Conflict of interests may exist. Biased results may have resulted from the mismatching of groups at baseline.

Effects of interventions

See: Summary of findings for the main comparison Rituximab for relapsing-remitting multiple sclerosis

Primary outcomes

Efficacy

(1) Patients in the rituximab group (n = 69), as compared with those in the placebo group (n = 35), had a lower annualised rate of relapse which reached significance at 24 weeks (0.37 versus 0.84, P = 0.04) but not at 48 weeks (0.37 versus 0.72, P = 0.08).

(2) Patients who received rituximab had a reduction in total gadolinium-enhancing T1-weighted lesion counts at week 24 as compared with patients who received placebo (mean number 0.5 versus 5.5; relative reduction 91%, P < 0.001). There was a lack of data on the total number of gadolinium-enhancing T1-weighted lesions at one year since this study was designed to evaluate this primary endpoint only at 24 weeks.

Safety

(1) More patients in the rituximab group (78.3%) than in the placebo group (40.0%) had infusion-associated adverse events, within the 24 hours after the first infusion, although acetaminophen (at a dose of 1 g) and diphenhydramine hydrochloride (at a dose of 50 mg) were administered orally 30 to 60 minutes before each infusion as premedication. Most of the infusion-associated adverse events (92.6%) in the rituximab group were mild to moderate (grade 1 or 2) in severity (the grades correspond to the Common Terminology Criteria for Adverse Events, version 3.0 (Cancer Therapy Evaluation Program 2006)). These included chills, headache, nausea, pyrexia, pruritus, fatigue, throat irritation, and pharyngolaryngeal pain. No grade 4 events associated with infusion were reported. The incidence of any infection was similar in the placebo group (71.4%) and the rituximab group (69.6%). The most common infections (occurring in > 10% of patients) in the rituximab group were nasopharyngitis, upper respiratory tract infections, urinary tract infections and sinusitis. Only urinary tract infections (14.5 versus 8.6%) and sinusitis (13.0% versus 8.6%) were more common in the rituximab group.

(2) Serious adverse events were reported in 14.3% of patients in the placebo group and 13% of patients in the rituximab group. Infection-associated serious adverse events were reported in 5.7% of patients in the placebo group and 2.9% of patients in the rituximab group. Two serious infection related adverse events (gastroenteritis and bronchitis) occurred in the rituximab group. No clinically significant opportunistic infections were reported.

(3) A total of 5.7% of the patients in the placebo group and 4.3% of the patients in the rituximab group withdrew from the study because of adverse events.

Secondary outcomes

The secondary outcomes (the number of patients with disability progression, the time to confirmed disease progression, and mean change in QoL) in this review were not included as outcomes in the included trial.

See: Summary of findings for the main comparison.

Discussion

Summary of main results

This systematic review included only one study (Hauser 2008) involving 104 adult patients with RRMS over a period of 48 weeks. It primarily evaluated a single course of intravenous rituximab at a dose of 1000 mg on days 1 and 15 versus placebo on inflammatory brain lesions, relapse and safety.

We were unable to perform a meta-analysis. The results of this trial showed that rituximab significantly reduced the total gadolinium-enhancing T1-weighted lesion counts (0.5 versus 5.5, a relative reduction of 91%, P < 0.001) and the annualised rate of relapse (0.37 versus 0.84, P = 0.04) at week 24 but that it did not significantly reduce the annualised rate of relapse at week 48 (0.37 versus 0.72, P = 0.08). Mild-to-moderate infusion-associated adverse events such as chills, headache, nausea, pyrexia, pruritus, fatigue, throat irritation and pharyngolaryngeal pain and infection-associated adverse events such as urinary tract infections and sinusitis were common. Short-term treatment with rituximab using a single course at a dose of 1000 mg intravenously was safe and well tolerated by most patients with RRMS. However, the high risk of attrition bias that resulted from the high rate of dropouts (40.0% in the placebo group and 15.9% in the rituximab group) at week 48 made the results unconvincing.

Overall completeness and applicability of evidence

In this review, it was difficult to answer the question whether rituximab was effective for MS. We are unable to give any recommendation for clinical practice on the use of rituximab for adult patients with RRMS. Only one study with relatively poor methodological quality was included. Not all primary or secondary outcomes were measured and subgroup and sensitivity analyses could not be performed as planned.

Quality of the evidence

There was not sufficient evidence because only one study with a short-term efficacy assessment on the primary endpoint was included in the review. The primary aim of the trial was to evaluate the MRI outcome endpoint over 24 weeks with a single course of rituximab (on days 1 and 15). The results were limited because of the high rate of dropouts (24.0%). The methodology used for random sequence generation and allocation concealment were unclear in this trial.

Potential biases in the review process

An extensive, comprehensive search was undertaken to limit bias in the review process, however only one RCT was retrieved. The two authors' independent assessments of the eligibility of studies for inclusion in this review and the extraction of data minimised the potential for additional bias beyond that detailed in the risk of bias tables. The authors of this review had no conflicts of interest.

Agreements and disagreements with other studies or reviews

Recently a systematic review (Castillo-Trivino 2013) included all available clinical trials irrespective of the types of studies to evaluate the efficacy and safety of rituximab for MS. Four studies in patients with RRMS or primary progressive MS were reviewed. The conclusions were based on qualitative synthesis without fully considering the potential influences of bias on the internal validity of the results.

Authors' conclusions

Implications for practice

Due to the limited quality of the available studies, there is not sufficient evidence to support the use of rituximab as a disease-modifying therapy for RRMS. The beneficial effects of rituximab for RRMS remain inconclusive. However, short-term treatment with a single course of rituximab was safe for most patients with RRMS. The most common infusion-associated adverse events included chills, headache, nausea, pyrexia, pruritus, fatigue, throat irritation and pharyngolaryngeal pain. Infection-associated adverse events such as nasopharyngitis, upper respiratory tract infections, urinary tract infections and sinusitis were also common.

Implications for research

The potential benefits of rituximab for treating RRMS remain to be evaluated in large-scale studies that are of high quality. Long-term safety needs to be assessed. Disability progression and quality of life should be addressed in future research. We are waiting for the publication of an ongoing trial.

Acknowledgements

We wish to thank Andrea Fittipaldo, Trials Search Coordinator, and Liliana Coco, Managing Editor of the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group for their help and support in developing this review. We thank all peer reviewers, and Loredana La Mantia, the quality advisor of the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group, for their constructive comments and suggestions for this review. We also thank Dr Han Wenjie and Dr Zhang Shihong for what they did previously for the first version of this review.

Data and analyses

Download statistical data

This review has no analyses.

Appendices

Appendix 1. Keywords for searching MS Group Register

{rituxan} OR {mabthera} OR {rituximab CD20 antibody} OR {IDEC-C2B8 antibody} OR {IDEC-C2B8} OR {rituxin} OR {rituximab} OR {{monoclonal} AND {antibod\*}}

AND {relapsing remitting} OR {relapsing-remitting } OR {remitting-relapsing} OR {remitting relapsing}

What's new

DateEventDescription
9 August 2013AmendedThe review author team was changed
9 August 2013New citation required but conclusions have not changedNo new studies were included in this update
9 August 2013New search has been performedSearch re-run

Contributions of authors

All correspondence: Dian He and Hongyu Zhou
Drafting of review versions: Dian He and Hongyu Zhou
Search for trials: Rui Guo and Chao Zhang
Obtaining copies of trial reports: Rui Guo and Fubo Zhang
Selection of trials for inclusion/exclusion: Dian He, Hongyu Zhou
Extraction of data: Dian He, Shuai Dong
Entry of data: Dian He, Shuai Dong
Interpretation of data analyses: Dian He, Hongyu Zhou

Declarations of interest

None known

Differences between protocol and review

In the current review, types of participants were expanded by adding the new McDonald criteria (Polman 2011). Other treatments in the 'Objectives' and 'Types of interventions' were defined as approved DMDs. Two secondary outcomes (increased disability measured with EDSS or MSFC) were removed because of a lack of such endpoints in clinical trials for MS. Two outcomes on safety (the number of patients with SAEs and the number of patients who withdrew or dropped out from the study because of AEs) were added. Three outcomes (the sum of the number of gadolinium-enhancing T1-weighted lesions, the number of patients with disability progression, and the time to confirmed disease progression) were rephrased because they are more formal. One subgroup analysis (different therapies, monotherapy or combination therapy) was added. All these changes in the methods from the protocol to the review have no effect on the review conclusions.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Hauser 2008

Methods

The trial was a phase 2, randomized, double-blind, placebo-controlled, 48-week trial conducted at 32 centres in the United States and Canada

Study start date: December 2004

Study completion date: December 2006

Follow-up period: 48 weeks

Participants

Inclusion criteria: (1) patients 18 to 55 years of age with a diagnosis of RRMS; (2) at least one relapse during the preceding year; (3) an entry score of 0 to 5.0 on the EDSS

Exclusion criteria: (1) disease categorized as secondary progressive, primary progressive, or progressive relapsing disease; (2) relapse within 30 days; (3) cyclophosphamide or mitoxantrone treatment within 12 months; (4) systemic corticosteroid therapy within 30 days; (5) treatment with interferon-beta, glatiramer acetate, natalizumab, plasmapheresis, or intravenous immune globulin within 60 days; (6) or non-lymphocyte-depleting immunosuppressive therapies within 90 days

Baseline characteristics were generally balanced between the two groups except for the proportion of patients without gadolinium-enhancing lesions (higher in the placebo group than in the rituximab group, 85.7% versus 63.8%, P = 0.02)

Summary of patient characteristics at baseline (placebo: G1 (n = 35), rituximab: G2 (n = 69)):

Age: G1 = 41.5±8.5 years, G2 = 39.6±8.7 years

Sex: female G1 = 29 (82.9%), G2 = 52 (75.4%); male G1 = 6 (17.1%), G2 = 17 (24.6%)

Disease duration: since onset G1 = 9.6±7.1 years, G2 = 9.6±6.4 years; since diagnosis G1 = 6.9±6.2 years, G2 = 6.2±5.2 years

Relapses in past year: 0 relapse G1 = 2 (5.7%), G2 = 4 (5.8%); 1 relapse G1 = 27 (77.1%), G2 = 52 (75.4%); 2 relapse G1 = 5 (14.3%), G2 = 8 (11.6%); 3 relapse G1 = 0, G2 = 4 (5.8%); ≥4 relapse G1 = 1 (2.9%), G2 = 1 (1.4%); median (range) G1 = 1.0 (0-5), G2 = 1.0 (0-4)

EDSS score: 0 G1 = 1 (2.9%), G2 = 2 (2.9%); 1.0-1.5 G1 = 8 (22.9%), G2 = 9 (13.0%); 2.0-2.5 G1 = 10 (28.6%), G2 = 24 (34.8%); 3.0-3.5 G1 = 7 (20%), G2 = 20 (29.0%); 4.0-4.5 G1 = 7 (20%), G2 = 11 (15.9%); 5.0 G1 = 2 (5.7%), G2 = 3 (4.3%); median (range) G1 = 2.5 (0-5), G2 = 2.5 (0-5)

Previous treatment with interferon-beta or glatiramer acetate: none or discontinued >6 months before study entry G1 = 21 (60%), G2 = 44 (63.8%); treatment within 6 months before study entry G1 = 14 (40%), G2 = 25 (36.2%)

Any key therapy for MS in previous 2 years: glatiramer acetate G1 = 8 (22.9%), G2 = 18 (26.1%); interferon beta-1a G1 = 16 (45.7%), G2 = 24 (34.8%); interferon beta-1b G1 = 5 (14.3%), G2 = 13 (18.8%); methylprednisolone or methylprednisolone sodium succinate G1 = 8 (22.9%), G2 = 19 (27.5%); natalizumab G1 = 2 (5.7%), G2 = 5 (7.2%)

Any key therapy for MS: G1 = 27 (77.1%), G2 = 54 (78.3%)

Gadolinium-enhancing lesions: 0 lesions G1 = 30 (85.7%), G2 = 44 (63.8%); 1 lesion G1 = 2 (5.7%), G2 = 7 (10.1%); 2 lesions G1 = 2 (5.7%), G2 = 4 (5.8%); 3 lesions G1 = 0, G2 = 2 (2.9%); ≥4 lesions G1 = 1 (2.9%), G2 = 11 (15.9%); mean lesions G1 = 0.3±0.8, G2 = 2.1±5.6; median lesions (range) G1 = 0 (0-4), G2 = 0 (0-36)

Volume of lesions detected on MRI: on gadolinium-enhanced MRI, mean G1 = 29.2±127.5 mm3, G2 = 211.6±702.2 mm3; median G1 = 0, G2 = 0; on T2-weighted MRI, mean G1 = 5723.1±5514.8 mm3, G2 = 6452.2±8022.2 mm3; median G1 = 4032.0, G2 = 2878.5; on T1-weighted MRI, mean G1 = 717.6±1025.0 mm3, G2 = 784.2±1206.4 mm3; median G1 = 369.0, G2 = 211.0

Interventions

Experimental group: 1000 mg intravenous infusions of rituximab on study days 1 and 15, before each infusion, acetaminophen (at a dose of 1 g) and diphenhydramine hydrochloride (at a dose of 50 mg) were administered orally 30 to 60 minutes beforehand as premedication

Control group: 1000 mg intravenous infusions of placebo on study days 1 and 15, before each infusion, acetaminophen (at a dose of 1 g) and diphenhydramine hydrochloride (at a dose of 50 mg) were administered orally 30 to 60 minutes beforehand as premedication

Outcomes

The primary outcome measures: the sum of the number of gadolinium-enhancing lesions on serial T1-weighted MRI brain scans at weeks 12, 16, 20, and 24. Lesions that persisted for more than 4 weeks were counted more than once.

Secondary outcome measures: (1) the total number of new gadolinium-enhancing lesions observed on serial T1-weighted MRI brain scans at weeks 12, 16, 20, and 24 (lesions persisting for more than 4 weeks were counted only once); (2) the change from the baseline lesion volume on T2-weighted MRI scans; (3) the proportion of patients with relapses at week 24 and week 48; (4) the annualised rate of relapse from week 0 to week 24 and week 0 to week 48; (5) safety. Relapse was defined as new or recurrent neurologic symptoms that were consistent with MS, lasted for at least 48 hours, and were preceded by a relatively stable or improving neurologic state for at least 30 days.

Notes

The study was originally designed to enroll 280 patients but before the primary endpoint at week 24, the sample-size target was reduced to 99 patients. With such a sample size the study would have 70% power at a two-sided significance level of 0.05.

The study was designed jointly by Genentech and the investigators and supported by Biogen Idec and Genentech. Data were collected by the investigators and held and analysed by Genentech. ClinicalTrials.gov Identifier: NCT00097188.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote: "Patients were randomly assigned in a 2:1 ratio to receive rituximab or placebo, and they were hierarchically stratified according to study site, status with respect to previous treatment with interferon beta or glatiramer acetate (either no treatment or discontinuation of medication ≥6 months previously versus treatment within the previous 6 months), and baseline disease severity according to the Expanded Disability Status Scale (EDSS) score (≤2.5 versus >2.5)".

Comment: the authors did not mention the specific method of random sequence generation. We wrote to the principal author (hausers@neurology.ucsf.edu) for the methodological information, but we got no reply. The risk of selection bias was unclear.

Allocation concealment (selection bias)Unclear riskThe authors did not mention the specific method of allocation concealment. We wrote to the principal author but we got no reply. The risk of selection bias was unclear.
Blinding (performance bias and detection bias)
All outcomes
Low risk

Quote: "This trial was double-blinded. Each site had both a treating investigator and an examining investigator. The treating investigator was the safety assessor, and the examining investigator was the efficacy assessor. Staff members from a central MRI reading center who were unaware of the data evaluated all scans. Data were collected by the investigators and held and analyzed by Genentech."

Comment: the participants, personnel and the outcomes assessors in this study were blinded to the allocated interventions. The risks of performance bias and detection bias were low.

Incomplete outcome data (attrition bias)
All outcomes
High risk

According to the table showing study sample and reasons for study discontinuation, of the 104 patients 96 (92.3%) completed 24 weeks, and 79 patients (76.0%) completed 48 weeks; 66 (95.7%) in the rituximab group and 30 (85.7%) in the placebo group completed 24 weeks; 58 (84.1%) in the rituximab group and 21 (60.0%) in the placebo group completed 48 weeks; 11 patients (15.9%) in the rituximab group and 14 patients (40.0%) in the placebo group discontinued before week 48. Reasons for discontinuation (placebo: G1, rituximab: G2): death G1 0, G2 1 (1.4%); adverse events G1 = 0, G2 = 1 (1.4%); pregnancy G1 = 1 (2.9%), G2 0; lost to follow-up G1 = 2 (5.7%), 2 (2.9%); patient's decision G1 = 4 (11.4%), G2 = 0; physician's decision G1 = 3 (8.6%), G2 = 3 (4.3%); relapse G1 = 2 (5.7%), G2 = 2 (2.9%); initiation of excluded therapy G1 = 2 (5.7%), G2 = 2 (2.9%). A last observation carried forward imputation strategy was used for the missing data. The intention-to-treat principle was used for analyses.

Comment: a risk of attrition bias could have resulted from the high rate of dropouts (24%) over the period of 48 weeks and the imbalance in the reasons for discontinuation between the two groups. Although a last observation carried forward imputation strategy was used for the missing data and the intention-to-treat principle was used for analyses, the high rate of dropouts had a potential impact on the results. Generally, the higher the ratio of participants with missing data to participants with events, the greater potential there is for bias, especially for the high frequency of events. The potential impact of missing continuous outcomes increases with the proportion of participants with missing data. Both MS relapse and the occurrence of gadolinium-enhancing T1-weighted lesions are common events. The risk of attrition bias was high.

Selective reporting (reporting bias)Low riskAll listed outcomes were reported adequately. The risk of reporting bias was low
Other biasUnclear risk

Quote: "The study was designed jointly by Genentech and the investigators"

Comment: conflict of interests may exist

Quote: "At baseline the proportion of patients without gadolinium-enhancing lesions was greater in the placebo group than in the rituximab group (85.7% versus 63.8%, P = 0.02)"

Comment: this may have led to biased results

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Bar-Or 2008An open-label trial
Naismith 2010An uncontrolled trial

Characteristics of ongoing studies [ordered by study ID]

NCT01569451

Trial name or titleA Double Blinded, Placebo Controlled, Randomized Study Comparing Rituximab Induction Therapy Followed by Glatiramer Acetate Therapy to Glatiramer Acetate Monotherapy in Patients With Relapsing Forms of Multiple Sclerosis
MethodsNot yet assessed
Participants

Inclusion criteria:

(1) 18 through 55 years of age

(2) Patients with CIS demonstrating one unifocal neurological event and at least 2 T2-weighted brain lesions measuring a minimum of 6 mm in diameter by MRI analysis; or a definite diagnosis of RMS, as defined by the 2005 revised McDonald criteria, and have had at least one clinically defined relapse within the past year or one GEL on an MRI within the past year

(3) Women of child-bearing potential must agree to practice an acceptable method of birth control

(4) No evidence of progressive multifocal leukoencephalopathy (PML) or primary central nervous system (PCNS) lymphoma

(5) Neurologically stable with no evidence of relapse or corticosteroid treatment within 30 days prior to randomisation

Exclusion criteria:

(1) ≥ 15 GELs on baseline MRI

(2) Treatment with interferon-β, natalizumab, or fingolimod within three months of randomisation; or treatment with mitoxantrone, cyclophosphamide, or any other chemotherapeutic agent for MS or malignancy within 12 months of randomisation; or any prior treatment with alemtuzumab or cladribine

(3) Attenuated live virus vaccination within 4 weeks of randomisation; or positive urine and serum pregnancy test at screening or baseline visit

(4) Unable to tolerate GA; or inability to undergo MRI scans or history of hypersensitivity to gadolinium- diethylenetriamine penta-acetic acid (DTPA)

(5) History of cardiac arrhythmias, angina or any other significant cardiac abnormalities; or history of clinically significant chronic disease of the immune system or a known immunodeficiency syndrome (HIV) other than MS; or history or presence of malignancy (except basal cell carcinoma); or positive for any evidence of past, or current, hepatitis B or C infection

(6) White blood cell count of less than 2.5x109/L or lymphocyte count below 0.4x109/L

(7) Clinically significant alcohol or drug abuse within past two years; or any medical, psychiatric or other condition that could result in a subject not being able to give fully informed consent or to comply with the protocol requirements

(8) Participation in any clinical study evaluating another investigational drug or therapy within three months prior to randomisation

Interventions

Intervention group:

(1) Intravenous (IV) infusion of 1000 mg of rituximab on study days 1 (baseline visit) and 15

(2) Glatiramer acetate 20 mg injected subcutaneously daily

Active comparator:

(1) intravenous (IV) infusion of placebo (normal saline) on study days 1 (baseline visit) and 15

(2) Glatiramer acetate 20 mg injected subcutaneously daily

Outcomes

Primary outcome measures: number of disease-free patients. Defined as patients without new lesions on brain MRI using the combined unique lesion approach (CUL), without sustained change in EDSS score over any 3-month period and without relapse

Secondary outcome measures:

(1)Time to treatment failure

(2) Percentage of subjects that fail treatment

(3) Proportion of relapse-free subjects

(4) Frequency of corticosteroid use

(5) Percentage of subjects who experience multiple relapses

(6) Number of patients that develop sustained accumulation of disability

(7) Change from baseline to the end of study on the Multiple Sclerosis Functional Composite (MSFC) z-score

(8) Percentage of subjects worsening one point or more on the Patient Determined Disease Steps (PDDS) questionnaire

(9) Change in mean score on performance scales

Starting dateFebruary 2012
Contact information

Mimi Burch: University of Colorado Hospital, Aurora, Colorado, United States, 80045. Phone: 303-724-6632; Email address: Mimi.Burch@ucdenver.edu

Nicole Gendelman: Phone: 303-724-2197; Email address: Nicole.Gendelman@ucdenver.edu

Principal investigator: Timothy Vollmer, MD. University of Colorado, Denver

Notes

Other Study ID Numbers: 10-1143

http://clinicaltrials.gov/ct2/show/NCT01569451

Ancillary