The Effect of Disease-Modifying Drugs on Brain Atrophy in Relapsing-Remitting Multiple Sclerosis: A Meta-Analysis (original) (raw)
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PloS one, 2015
A number of officially approved disease-modifying drugs (DMD) are currently available for the early intervention in patients with relapsing-remitting multiple sclerosis (RRMS). The aim of the present study was to systematically evaluate the effect of DMDs on disability progression in RRMS. We performed a systematic review on MEDLINE and SCOPUS databases to include all available placebo-controlled randomized clinical trials (RCTs) of RRMS patients that reported absolute numbers or percentages of disability progression during each study period. Observational studies, case series, case reports, RCTs without placebo subgroups and studies reporting the use of RRMS therapies that are not still officially approved were excluded. Risk ratios (RRs) were calculated in each study protocol to express the comparison of disability progression in RRMS patients treated with a DMD and those RRMS patients receiving placebo. The mixed-effects model was used to calculate both the pooled point estimate ...
Role of disease-modifying oral drugs in multiple sclerosis: A systematic review with meta-analysis
Revista Mexicana de Neurociencia
The purpose of the study was to evaluate the efficacy and safety of cladribine tablets compared with all oral therapies used in patients with relapsing-remitting multiple sclerosis (RRMS). A systematic review of the literature was conducted to identify published clinical trials about RRMS and a network meta-analysis was performed to determine the efficacy and safety of available treatments. We identified seven relevant studies, which were selected based on three criteria that allowed us to construct comparisons of efficacy and safety. Regarding the annualized relapse rate (ARR), there were no significant differences with respect to the decrease of this between cladribine tablets, dimethyl fumarate and fingolimod; although teriflunomide and cladribine tablets showed a significant difference. In relation to the mean number of gadolinium-enhanced T1 lesions, dimethyl fumarate showed a lower number of lesions (−0.85 [−1.21; −0.48]), as did cladribine tablets versus placebo. No statistically significant differences were identified between cladribine tablets and fingolimod (−0.08 [−0.35; 0.19]) and cladribine versus teriflunomide (−0.28 [−0.64; 0.08]). While comparing adverse events that caused discontinuation, cladribine tablets showed an adequate safety profile, which was quantitatively similar to the compared drugs. Cladribine tablets demonstrated efficacy in terms of decrease of ARR and gadolinium-enhanced T1 lesions; although there is no significant difference between cladribine tablets, fingolimod and teriflunomide, the ARR is a stronger measure of efficacy compared to the number of T1 lesions made in contrast with long-term RRMS. Cladribine also demonstrated an adequate safety and tolerability profile promoting therapeutic adherence.
Sample sizes for brain atrophy outcomes in trials for secondary progressive multiple sclerosis
Neurology, 2009
Background: Progressive brain atrophy in multiple sclerosis (MS) may reflect neuroaxonal and myelin loss and MRI measures of brain tissue loss are used as outcome measures in MS treatment trials. This study investigated sample sizes required to demonstrate reduction of brain atrophy using three outcome measures in a parallel group, placebo-controlled trial for secondary progressive MS (SPMS).
The Lancet Neurology, 2013
Background Siponimod is an oral selective modulator of sphingosine 1-phosphate receptor types 1 and type 5, with an elimination half-life leading to washout in 7 days. We aimed to determine the dose-response relation of siponimod in terms of its eff ects on brain MRI lesion activity and characterise safety and tolerability in patients with relapsingremitting multiple sclerosis. Methods In this double-blind, adaptive dose-ranging phase 2 study, we enrolled adults (aged 18-55 years) with relapsing-remitting multiple sclerosis at 73 medical centres in Europe and North America. We tested two patient cohorts sequentially, separated by an interim analysis at 3 months. We randomly allocated patients in cohort 1 (1:1:1:1) to receive once-daily siponimod 10 mg, 2 mg, or 0•5 mg, or placebo for 6 months. We randomly allocated patients in cohort 2 (4:4:1) to siponimod 1•25 mg, siponimod 0•25 mg, or placebo once-daily for 3 months. Randomisation was done with a central, automated system and patients and investigators were masked to treatment assignment. The primary endpoint was dose-response, assessed by percentage reduction in monthly number of combined unique active lesions at 3 months for siponimod versus placebo; this endpoint was analysed by a multiple comparison procedure with modelling techniques in all patients with at least one MRI scan up to 3 months. We assessed safety in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00879658.
Journal of Neurology Neurosurgery and Psychiatry, 1999
Objectives-To review the outcome measures commonly used in phase III treatment trials of relapsing-remitting multiple sclerosis and to introduce a method of data analysis which is clinically appropriate for the often reversible disability in this type of multiple sclerosis. Methods-The conventional end point measures for disability change are inadequate and potentially misleading. Those using the disability diVerence between study entry and completion do not take into account serial data or disease fluctuations. Rigid definitions of "disease progression" based on two measurements of change in disability several months apart, do not assess worsening after the defined "end point", nor the significant proportion of erroneous "treatment failures" which result from subsequent recovery from relapses that outlast the end point. Assessing attacks merely by counting their frequency ignores the variation in magnitude and duration. These problems can be largely circumvented by integrating the area under a disability-time curve (AUC), a technique which utilises all serial measurements at scheduled visits and during relapses to summarise the total neurological dysfunction experienced by an individual patient on any particular clinical scale during a study period. Conclusions-The "summary measure" statistic AUC incorporates both transient and progressive disability into an overall estimate of the dysfunction that was experienced by a patient during a period of time. It is statistically more powerful and clinically more meaningful than conventional methods of assessing disability changes, particularly for trials which are too short to expect to disclose major treatment eVects on irreversible disability in patients with a fluctuating disease. (J Neurol Neurosurg Psychiatry 1998;64:726-729)
Multiple sclerosis and related disorders, 2015
A reduction in relapse rate is the main primary outcome in most clinical trials in patients with multiple sclerosis (MS), with the effect of a treatment commonly expressed as relative risk reduction for this outcome. Physicians often assume that a drug with a higher relative risk reduction demonstrated in one trial is more effective than a drug with a lower relative risk reduction in another, and may pass this idea on to younger physicians and to patients. The use of the relative risk reduction as a measure of drug efficacy can be misleading, as it depends on the nature of the population studied: a treatment effect characterized by a lower relative risk reduction may be more clinically meaningful than one with a higher relative risk reduction. This concept is especially important with regard to clinical trials in patients with MS, where relapse rates in placebo groups have been declining in recent decades. Direct, head-to-head comparisons are the only way to compare the efficacy of ...
BMC Neurology
Background: Multiple sclerosis (MS) is a chronic immune mediated disease and the progressive phase appears to have significant neurodegenerative mechanisms. The classification of the course of progressive MS (PMS) has been re-organized into categories of active vs. not active inflammatory disease and the presence vs. absence of gradual disease progression. Clinical trial experience to date in PMS with anti-inflammatory medications has shown limited effect. Andrographolide is a new class of anti-inflammatory agent, that has been proposed as a potential drug for autoimmune disorders, including MS. In the present trial, we perform an exploratory pilot study on the efficacy and safety of andrographolide (AP) compared to placebo in not active PMS.
Advances in therapy, 2014
No head-to-head trials have compared the efficacy of the oral therapies, fingolimod, dimethyl fumarate and teriflunomide, in multiple sclerosis. Statistical modeling approaches, which control for differences in patient characteristics, can improve indirect comparisons of the efficacy of these therapies. No evidence of disease activity (NEDA) was evaluated as the proportion of patients free from relapses and 3-month confirmed disability progression (clinical composite), free from gadolinium-enhancing T1 lesions and new or newly enlarged T2 lesions (magnetic resonance imaging composite), or free from all disease measures (overall composite). For each measure, the efficacy of fingolimod was estimated by analyzing individual patient data from fingolimod phase 3 trials using methodologies from studies of other oral therapies. These data were then used to build binomial regression models, which adjusted for differences in baseline characteristics between the studies. Models predicted the ...