Description of the condition
Multiple sclerosis (MS) is a chronic immune-mediated, inflammatory, demyelinating, neurodegenerative disorder of the central nervous system (CNS) in which immunoreactions lead to myelin sheath attack and axons injury. It is characterised by recurrent relapses and/or progression, typically striking adults during the primary productive time of their life and ultimately leading to severe neurological disability.
(1) The characteristics of MS
The overall incidence rate of MS in the world was 3.6 cases per 100,000 person-years in women and 2.0 cases in men (Alonso 2008). It is estimated to affect 2.1 million people worldwide (National MS Society 2009). There are four clinical phenotypes of MS. Initially, more than 80% of individuals with MS experience a relapsing-remitting disease course (RRMS) characterised by clinical exacerbations of neurologic symptoms followed by complete or incomplete remission (Lublin 1996). After 10 to 20 years, or median age 39.1 years, about half of these people gradually accumulate irreversible neurologic deficits with or without clinical relapses (Confavreux 2006), which is known as secondary progressive MS (SPMS). Another 10% to 20% of individuals with MS are diagnosed with primary progressive MS (PPMS), clinically defined as a disease course without any clinical attacks or remission from onset (Lublin 1996). A significantly rarer form is progressive relapsing MS (PRMS), which initially presents as PPMS; however, during the course of the disease, these individuals develop true neurologic exacerbations (Tullman 2004). Growing evidence supports an inflammatory pathology occurring during the early relapsing stage of MS, and neurodegenerative pathology dominates the later progressive stage of the disease. Gray matter (GM) damage was shown to be frequent and extensive, and more pronounced in the progressive disease phases. Its underlying pathology is different from white matter damage in MS (Hulst 2011). Diffuse meningeal inflammation through B-cell follicle-like structures is associated with cortical pathology and an accelerated clinical course in SPMS (Fernández 2012). GM damage occurs early in the disease course, and correlates with future MS-related disability (Fernández 2012).
(2) The socioeconomic burden of MS
MS causes major socioeconomic burden for the individual patient and for society. Productivity costs are a far more important economic factor, especially due to reduced employment, which are enhanced by the early age of disease onset (Jennum 2012). Mobility problems represent a considerable personal and social burden both financially and in terms of quality of life (Pike 2012). From a patient's perspective an MS relapse is associated with a significant increase in economic costs as well as a decline in health-related quality of life and functional ability (Oleen-Burkey 2012). Direct costs are mainly due to medical care in earlier stages of disease; indirect costs are mainly due to disability and productivity loss in later stages (Naci 2010). 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 2012).
(3) The key issues of current disease-modifying therapies (DMTs) for MS
DMTs for MS currently aim to specifically reduce inflammation in relapsing MS and promote neuroprotection and neurorepair in progressive MS. As the most promising endpoints, Magnetic Resonance Imaging (MRI) measures (the percentage brain volume change (PBVC)) (Barkhof 2009; van den Elskamp 2010), T1 hypointensity (black holes) and magnetisation transfer ratio (Cadavid 2009; Zivadinov 2012)), and optical coherence tomography findings (the thickness of the retinal nerve fibre layer (RNFL)) (Fernández 2012; Lidster 2012) are or will be used in neuroprotection trials. Freedom from disease, defined as freedom from relapses, the absence of disability progression, and freedom from gadolinium-enhancing T1 or new T2 lesions detected by MRI , is used as the measure of DMTs' success (Fox 2012). However, relapses, disability progression and increasing disability may still occur in patients receiving first-line DMTs with frequent parenteral administration and even second-line DMTs with the risk of severe adverse events. Furtheremore, administration of interferon beta was not associated with a reduction in progression of disability among patients with RRMS (Shirani 2012). So far there is no DMT available that can completely halt the neurodegenerative changes associated with the disease. The unmet needs highlight the reasons for developing new DMTs for MS, focusing on superior efficacy, ease of administration, good tolerability, and long-term safety. Therefore, alternative MS treatments with oral routes of administration and new modes of action are needed to expand the current treatment repertoire, increase patient satisfaction and adherence, and thereby improve efficacy.
Description of the intervention
Laquinimod, an oral quinoline-3-carboxamide, is a derivative of linomide (roquinimex) but does not have the adverse effects associated with linomide. It has dual properties in experimental autoimmune encephalomyelitis (EAE): immunomodulatory and neuroprotective capacities (Aharoni 2012). Analyses in EAE demonstrate that laquinimod reduces infiltration of leukocytes into sites of inflammation in the CNS, and induces a T-helper-1(Th1) cytokine to Th2/3 cytokines shift, without inducing much immunosuppression (Brunmark 2002; Zou 2002; Yang 2004). Laquinimod might protect myelin and axons by decreasing interleukin (IL)-17 levels and impairing the migratory capacity of lymphocyte (Wegner 2010) and modulated B cell markers, mainly by increasing the regulatory ones CD25, IL10 and CD86, and decreased IL4, while increasing IL10 and TGFβ in both B and T cells, in a B cell-mediated manner (Toubi 2012). Laquinimod reduced trafficking of proinflammatory monocytes into the CNS (Mishra 2012) and skewed monocytes toward a regulatory phenotype and also acted via modulation of brain-derived neurotrophic factor (BDNF), which may contribute to neuroprotection in MS patients (Thöne 2012). Laquinimod modulates adaptive T cell immune responses via its effects on cells of the innate immune system, and may not influence T cells directly (Schulze-Topphoff 2012). Meanwhile, it downregulates the astrocytic pro-inflammatory response, which might have protective effects on myelin, oligodendrocytes and axons (Brück 2012).
Preclinical studies have shown that laquinimod reduces inflammation in the CNS, decreases demyelination, and prevents axonal damage in EAE mice (Brück 2011). These results translate its immunomodulatory and CNS-protective effects into clinical benefits in patients withe RRMS. Recent findings from clinical trials indicate that laquinimod has significant effects in reducing relapse rate and has more pronounced effects in reducing sustained disability progression as well as brain atrophy, with a good safety profile.
How the intervention might work
A randomised, double-blind, parallel-group, placebo-controlled study showed oral laquinimod in a dosage of 0.3 mg daily was well tolerated and effective in suppressing development of active lesions in relapsing MS. A phase Ⅱ study (LAQ/5062) showed 0.6 mg per day laquinimod significantly reduced MRI-measured disease activity and was well tolerated in patients with RRMS. The extension trial of LAQ/5062 study confirmed the good efficacy and the excellent safety and tolerability profiles of laquinimod 0.6 mg/day. In a randomised, double-blind, parallel-group, placebo-controlled, phase Ⅲ study (ALLEGRO), oral laquinimod administered 0.6 mg once daily slowed the progression of disability and reduced the rate of relapse in patients with RRMS.
Why it is important to do this review
A randomised, double-blind, parallel-group, phase Ⅲ study (BRAVO) comparing the effect of oral laquinimod 0.6 mg/day with the effect of placebo as well as with the effect of Interferon β-1a (Avonex®) is expected to be published in the near future. The long-term extensions (open-label studies) of the ALLEGRO study, the BRAVO study, and the LAQ/5062 and LAQ/5063 study investigating the long-term safety, tolerability and effect of laquinimod monotherapy (0.6 mg orally once daily) are currently ongoing. A randomised, double-blind, parallel-group, placebo-controlled, phase Ⅲ study (CONCERTO) evaluating the efficacy, safety and tolerability of two oral doses of laquinimod (0.6 mg/day or 1.2 mg/day) in subjects with RRMS will start in January 2013.
No systematic review currently exists in the peer-reviewed literature that focuses on laquinimod for patients with MS. A systematic review of all randomised controlled trials is warranted to evaluate the effectiveness and safety of laquinimod for MS.
To assess the effectiveness and safety profile of laquinimod as monotherapy or combination therapy versus placebo or approved disease-modifying drugs (DMDs) (IFN-β, glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide) for modifying disease course in patients with multiple sclerosis (MS).
Criteria for considering studies for this review
Types of studies
All randomised double-blind, controlled, parallel clinical trials (RCTs) evaluating laquinimod, as monotherapy or combination therapy, versus placebo or any other treatment for patients with MS. We will exclude uncontrolled, non-randomised or quasi-randomised trials. We will exclude trials with a length of follow-up shorter than one year.
Types of participants
We will include patients aged over 18 years with a definite diagnoses of MS according to Poser's (Poser 1983) or McDonald's (McDonald 2001; Polman 2005; Polman 2011) criteria, any clinical phenotypes categorised according to the classification of Lublin and Reingold (Lublin 1996), and EDSS scores ≤ 6.0 with or without progression.
Types of interventions
Experimental intervention: treatment with laquinimod orally, as monotherapy or combination therapy, without restrictions regarding dosage, administration frequency and duration of treatment.
Control intervention: placebo or other treatments (IFN-β, glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide) for MS.
Types of outcome measures
We will assess the following primary outcomes, measured in the treatment phase and at the completion of follow-up versus baseline.
- The annualised rate of relapse at one year (or later), defined as the mean number of confirmed relapses per patient, adjusting for the duration of follow-up to annualise it. Confirmed relapse is defined as the occurrence of new symptoms or worsening of previously stable or improving symptoms and signs not associated with fever or infection, occurring at least 30 days after the onset of a preceding relapse, lasting more than 24 hours. The relapse should be verified by objective neurologic changes as indicated by an increase of at least 0.5 point in Expanded Disability Status Scale (EDSS) score or at least one grade in two or more functional systems or at least two grades in one functional system.
- The proportion of patients free of disability progression as assessed by the EDSS (Kurtzke 1983) at one year (or later). We will accept definitions of confirmed disability progression reported in the included trials.
The number of patients with adverse effects, number of patients with serious adverse events and number of patients who withdrew or dropped out from the study because of adverse events at one year (or later).
We will assess the following secondary outcomes, measured in the treatment phase and at the completion of follow-up versus baseline.
- The sum of the number of gadolinium-enhancing T1-weighted lesions at one year (or later). (Lesions that persisted for more than 4 weeks will be counted more than once).
- The time to confirmed disease progression at one year (or later).
- The percentage brain volume change (PBVC) at one year (or later).
Search methods for identification of studies
No language restrictions will be applied to the search.
The Review Group's Trials Search Co-ordinator will search the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Trials Register which, among other sources, contains CENTRAL, MEDLINE, EMBASE, CINAHL, LILACS, PEDRO and Clinical trials registries (http://clinicaltrials.gov).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 trials for this review are listed Appendix 1.
Searching other resources
- We will check reference lists of published reviews and retrieved articles for additional trials.
- We will search reports (2004 onwards) from the MS Societies (National Multiple Sclerosis Society (United States, United Kingdom)) and the Congress of the European and Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS and ACTRIMS).
- We will communicate personally with investigators participating in trials of laquinimod.
- We will contact Teva Pharmaceutical Industries (http://www.tevapharm.com/Pages/default.aspx) in an effort to identify further studies.
Data collection and analysis
Selection of studies
Titles and abstracts of the citations retrieved by the literature search will be screened independently for inclusion/exclusion by two review authors (He, Dong). We will select the full text of potentially relevant studies for further assessment. We will evaluate independently the eligibility of these studies on the basis of information available in the published data. Papers that do not meet the inclusion criteria will be listed in the 'Characteristic of excluded studies' table with the reason for omission. Any disagreement regarding inclusion will be resolved by discussion, or by referral to a third assessor (Chu) if necessary.
Data extraction and management
Two review authors (He, Dong) will independently extract data from the selected trials using standardised forms. Information about study design, participants, intervention and outcome measures will be extracted. We will contact principal investigators of included studies to obtain additional data or confirmation of methodological aspects of the study. Disagreements will be discussed and resolved by consensus among review authors.
Assessment of risk of bias in included studies
The methodological criteria will be based on the Cochrane Handbook for Systematic Reviews of Interventions, version 5.1.0 (Higgins 2011). Two review authors (He, Dong) will evaluate independently the methodological quality of the studies using the 'Risk of bias' tool under the domains of sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome and other biases. We will exclude studies at a high risk of bias. Disagreements among the review authors on the methodological quality of the identified studies will be discussed and resolved by consensus.
Measures of treatment effect
The pre-set outcomes in this protocol involve counts and rates, dichotomous and continuous data, 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, we will use the mean difference to compare the difference in the mean number of events (possibly standardised to a unit time period) experienced by participants in the intervention group compared with participants in the control group. Both MS relapse and gadolinium-enhancing T1-weighted lesions are common events, so we will use the mean difference as the measure of treatment effect.
For continuous outcomes, we will calculate the mean difference or the standardised mean difference (SMD) with 95% confidence intervals (CI). Standard deviation will be calculated from CI, or t-tests when CI is not reported. The percentage brain volume change (PBVC) is a continuous outcome, and the mean difference will be used as the measure of treatment effect.
For dichotomous outcomes, we will calculate individual and pooled statistics as relative ratios (RR) or odds ratios (OR), risk difference (RD) (also called the absolute risk reduction) and the number needed to treat (NNT). Both the proportion of patients free of disability progression and the number of patients with adverse effects are dichotomous outcomes and we will use relative ratios (RR) as the measure of treatment effect.
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 belongs to time-to-event data, and we will used relative ratios (RR) as the measure of treatment effect.
Unit of analysis issues
Some RCTs on laquinimod for MS are multi-arm studies with two experimental intervention groups (0.3 mg/day, 0.6 mg/day or 1.2 mg/day of laquinimod) and a common control group, involving repeated observations on participants. The pre-set outcome measures in this protocol involve events that may re-occur. We will combine all relevant experimental intervention groups (0.3 mg/day, 0.6 mg/day or 1.2 mg/day) 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. Meanwhile, we will perform separate analyses based on the pre-set outcomes in this protocol and different periods of follow-up. Counts of common events (MS relapse and gadolinium-enhancing T1-weighted lesions) will be treated in the same way as continuous outcome data.
Dealing with missing data
If sufficient data are not available from published reports, we will contact the study authors for further details. For dichotomous outcomes, we will analyse the missing data using an intention-to-treat analysis. For continuous outcomes, we will perform sensitivity analyses to assess the sensitivity of the results to the assumptions that are made. Best- and worst-case scenario will be considered for taking into account missing data.
Assessment of heterogeneity
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 also be evaluated. When pooling trials in meta-analyses, we will calculate the I
Assessment of reporting biases
If sufficient RCTs are identified, we will examine potential publication bias using a funnel plot. For continuous outcomes, the standard error will be used as the vertical axis and the mean differences will be used as the horizontal axis in funnel plots. For dichotomous outcomes, the odds ratios or risk ratios will be plotted on a logarithmic scale as the horizontal axis and the standard error will be used as the vertical axis.
When clinically and methodologically homogeneous RCTs are identified in future updates and heterogeneity tests suggest an I
Subgroup analysis and investigation of heterogeneity
If possible, we intend to undertake subgroup analyses according to:
- different therapies (e.g. monotherapy, combined IFN-β therapy or combined glatiramer acetate therapy);
- different MS patients (e.g. patients with RRMS or patients with progressive MS);
- duration of follow-up (e.g. 1 year, between 1 and 2 years, more than 2 years);
- baseline EDSS scores (e.g. ≤ 3.5, between 3.5 and 6);
- dosage level (e.g. 0.3mg/day, 0.6mg/day or 1.2 mg/day);
- different duration of MS (e.g. 5 years, more than 5 years).
Where possible, we will conduct sensitivity analysis to assess the influence on results of fixed-effect model versus random-effects model assumptions and of including trials at high risk of bias as well as the effects of analysing by intention to treat and the effect size (for dichotomous outcomes, relative ratios versus odds ratio; and for continuous outcomes, the mean difference versus the standardised mean difference). We will treat counts of common events in the same way as continuous outcome data.
We thank the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Review Group editorial team for advice and support.
Appendix 1. Search terms for Specialised Register
Contributions of authors
All correspondence: Dian He and Lan Chu
Drafting of review versions: Dian He and Lan Chu
Search for trials: ZhanHui Feng and Kai Han
Obtaining copies of trial reports: Shan Wu and Xiangdong Gao
Selection of trials for inclusion/exclusion: Dian He and Shuai Dong
Extraction of data: Dian He and Shuai Dong
Entry of data: Dian He and Shuai Dong
Interpretation of data analyses: Dian He and Lan Chu
Declarations of interest