***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more The assessment of brain volume change with serial MRI provides an objective measure of an important component of the pathology of multiple sclerosis . Glatiramer acetate ( GA ) has a beneficial effect on clinical and MRI measures of disease activity and burden in patients with relapsing-remitting ( RR ) multiple sclerosis . This study investigated the impact of GA treatment on the development of brain atrophy in RR multiple sclerosis patients . The study consisted of a 9-month , double-blind , placebo-controlled phase followed by a 9-month open-label phase . Patients were r and omized to receive either 20 mg GA or placebo by daily subcutaneous injections  and underwent brain MRI scans every month during the first phase , and every 3 months during the second phase of the study . Using a semi-automated segmentation technique based on local thresholding , brain volume was measured from seven contiguous periventricular slices from the scans obtained at baseline , the end of the double-blind phase and the end of the study . From the original trial cohort , image sets from 113 out of 119 patients r and omized to  GA , and 114 out of 120 r and omized to placebo treatment were evaluated . Brain volume was significantly correlated with patients ' disability at each time-point . No significant differences between placebo- and GA-treated patients were found for baseline brain volume and rate of brain volume change over the study , even though a possible late trend for treatment with GA to retard the loss of brain volume was observed . There was a significant , but modest , correlation between MRI activity during the double-blind phase , and brain volume change over the entire study among patients originally treated with placebo . The modest correlation between enhancement frequency and brain atrophy loss indicates that the suppression of inflammatory activity in RR multiple sclerosis patients is not fully and rapidly associated with a similar effect on the global neurodegenerative processes . This study also suggests that any effect of GA in preventing brain volume decrease is not evident early following institution of treatment Background : Episodic inflammation in the CNS during the early stages of MS results in progressive disability years later , presumably due to myelin and axonal injury . MRI demonstrates ongoing disease activity during the early disease stage , even in some patients who are stable clinical ly . The optimal MRI measure for the destructive pathologic process is uncertain , however . Methods : In this post-hoc study ,  MRI scans were analyzed from patients with relapsing MS participating in a placebo-controlled trial of interferon β-1a .  The brain parenchymal fraction , defined as the ratio of brain parenchymal volume to the total volume within the brain surface contour , was used to measure whole brain atrophy . The relationship between disease features and brain atrophy and effect of interferon β-1a were determined . Results : MS patients  had significant brain atrophy that worsened during each of 2 years of observation . In many patients , brain atrophy worsened without clinical disease activity . Baseline clinical and MRI abnormalities were not strongly related to the rate of brain atrophy during the subsequent 2 years . Treatment with interferon β-1a result ed in a reduction in brain atrophy progression during the second year of the clinical trial . Conclusions : Patients with relapsing-remitting MS have measurable amounts of whole brain atrophy that worsens yearly , in most cases without clinical manifestations . The brain parenchymal fraction is a marker for destructive pathologic processes ongoing in relapsing MS patients , and appears useful in demonstrating treatment effects in controlled clinical trials BACKGROUND Oral fingolimod , a sphingosine-1-phosphate-receptor modulator that prevents the egress of lymphocytes from lymph nodes , significantly improved relapse rates and end points measured on magnetic resonance imaging ( MRI ) , as compared with either placebo or intramuscular interferon beta-1a , in phase 2 and 3 studies of multiple sclerosis . METHODS In our 24-month , double-blind , r and omized study , we enrolled patients who had relapsing-remitting multiple sclerosis , were 18 to 55 years of age , had a score of 0 to 5.5 on the Exp and ed Disability Status Scale ( which ranges from 0 to 10 , with higher scores indicating greater disability ) , and had had one or more relapses in the previous year or two or more in the previous 2 years . Patients received oral fingolimod at a dose of 0.5 mg or 1.25 mg daily or placebo . End points included the annualized relapse rate ( the primary end point ) and the time to disability progression ( a secondary end point ) . RESULTS A total of 1033 of the 1272 patients ( 81.2 % ) completed the study . The annualized relapse rate was 0.18 with 0.5 mg of fingolimod , 0.16 with 1.25 mg of fingolimod , and 0.40 with placebo ( P<0.001 for either dose vs. placebo ) . Fingolimod at doses of 0.5 mg and 1.25 mg significantly reduced the risk of disability progression over the 24-month period ( hazard ratio , 0.70 and 0.68 , respectively ; P=0.02 vs. placebo , for both comparisons ) . The cumulative probability of disability progression ( confirmed after 3 months ) was 17.7 % with 0.5 mg of fingolimod , 16.6 % with 1.25 mg of fingolimod , and 24.1 % with placebo . Both fingolimod doses were superior to placebo with regard to MRI-related measures ( number of new or enlarged lesions on T(2)-weighted images , gadolinium-enhancing lesions , and brain-volume loss ; P<0.001 for all comparisons at 24 months ) . Causes of study discontinuation and adverse events related to fingolimod included bradycardia and atrioventricular conduction block at the time of fingolimod initiation , macular edema , elevated liver-enzyme levels , and mild hypertension . CONCLUSIONS As compared with placebo , both doses of oral fingolimod improved the relapse rate , the risk of disability progression , and end points on MRI . These benefits will need to be weighed against possible long-term risks . ( Clinical Trials.gov number , NCT00289978 . Background : The placebo-controlled phase of the PreCISe study showed that glatiramer acetate delayed onset of clinical ly definite multiple sclerosis ( CDMS ) in patients with clinical ly isolated syndrome and brain lesions on MRI . Objective : To compare the effects of early versus delayed glatiramer acetate treatment in the open-label phase of PreCISe . Methods : Patients with a clinical ly isolated syndrome suggestive of MS with unifocal manifestation and ≥2 T2-weighted brain lesions were r and omized to receive glatiramer acetate 20 mg/d  ( early-treatment , n=198 )  or placebo ( delayed-treatment , n=211 ) for 36 months or until conversion to CDMS , followed by open-label glatiramer acetate treatment for two years . Results : Early glatiramer acetate treatment reduced CDMS conversion risk by 41 % ( hazard ratio 0.59 , 95 % confidence interval 0.44–0.80 ; p=0.0005 ) versus delayed-treatment , and was associated with a 972-day delay ( 185 % ) in conversion to CDMS , less brain atrophy ( −28 % , p=0.0209 ) , fewer new T2 lesions/year ( −42 % , < 0.0001 ) and lower T2 lesion volume ( −22 % , p=0.0005 ) versus delayed treatment . Adverse events were consistent with the established safety profile of glatiramer acetate . Conclusions : Effects of early glatiramer acetate treatment on the rate of conversion to CDMS and on MRI measures of disease activity and lesion burden support initiating glatiramer acetate treatment soon after the first clinical symptoms suggestive of MS and continuing treatment to sustain benefits BACKGROUND In patients who present with clinical ly isolated syndromes suggestive of multiple sclerosis , interferon beta-1a is effective in delaying evolution to clinical ly definite disease and in reducing MRI-measured disease activity . We aim ed to assess whether this drug can also reduce the rate of brain volume decrease in such patients enrolled in the ETOMS ( early treatment of multiple sclerosis ) trial . METHODS MRI data for brain volume measurements at baseline , month 12 , and month 24 were available from 131 , 111 , and 112 patients assigned treatment ( 22 microg interferon beta-1a ) , and 132 , 98 , and 99 patients assigned placebo respectively .  Normalised brain parenchymal volume ( NBV ) at baseline and percentage brain volume changes ( PBVC ) were measured with a fully-automated segmentation technique . The primary endpoint was conversion to clinical ly definite multiple sclerosis due to clinical relapse . Analysis was by intention to treat . FINDINGS 41 ( 31 % ) of 131 patients on interferon beta-1a  and 62 ( 47 % ) of 132 on placebo converted to clinical ly definite multiple sclerosis ( odds ratio 0.52 [ 95 % CI 0.31 - 0.86 ] , p=0.0115 ) . Mean PBVC for patients on placebo was -0.83 % during the first year , -0.67 % during the second year , and -1.68 % during the entire study period . Respective values for treated patients were -0.62 % , -0.61 % , and -1.18 % . The changes in brain volume were significant in both groups at all timepoints . A significant treatment effect was detected for month 24 versus baseline values ( p=0.0031 ) . The number of new T2 lesions formed during the first year correlated weakly with PBVC during the second year . INTERPRETATION Early treatment with interferon beta-1a is effective in reducing conversion to clinical ly definite multiple sclerosis and in slowing progressive loss of brain tissue in patients with clinical ly isolated syndromes . The modest correlation between new lesion formation and brain volume decrease suggests that inflammatory and neurodegenerative processes are , at least partly , dissociated from the earliest clinical stage of multiple sclerosis onwards BACKGROUND The IMPROVE study demonstrated that the fetal bovine serum (FBS)- and human serum albumin (HSA)-free formulation of subcutaneous ( sc ) interferon ( IFN ) beta-1a had beneficial effects on the numbers of combined unique active magnetic resonance imaging ( MRI ) lesions in relapsing-remitting multiple sclerosis ( RRMS ) . Here we report additional MRI endpoints ( including post hoc analyses ) , and clinical efficacy , safety , and immunogenicity outcomes . METHODS Patients with active RRMS were r and omized ( 2:1 ) to  IFN beta-1a , 44 mcg sc three times weekly ( tiw ) ( n=120 ) , or placebo ( n=60 ) , for 16 weeks ( double-blind phase ) . All patients then received IFN beta-1a , 44 mcg sc tiw , for 24 weeks ( rater-blind phase ) . Patients underwent MRI brain scans every 4 weeks . RESULTS Compared with placebo , there was a 68 % reduction in the mean cumulative number of new gadolinium-enhancing lesions with IFN beta-1a as early as week 4 ( p<0.001 ) , and a 53 % reduction in the mean cumulative number of new T2 lesions as early as week 8 ( p=0.025 ; post hoc analyses ) . During the 16-week double-blind phase , the relapse rate was 0.14 ( 95 % confidence interval [ CI ] 0.09 - 0.23 ) with IFN beta-1a and 0.33 ( 95 % CI 0.22 - 0.52 ) with placebo ( p=0.010 ) . Safety outcomes were consistent with those expected with IFN-beta treatment . CONCLUSIONS The FBS/HSA-free formulation of sc IFN beta-1a has a beneficial impact on MRI and efficacy outcomes as early as 4 weeks after treatment initiation in patients with RRMS and has a safety profile consistent with previous trials of sc IFN beta-1a 
    Output:
    
DMD appear to be effective in attenuating brain atrophy in comparison to placebo and their benefit in delaying the rate of brain volume loss increases linearly with longer treatment duration