***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: INTRODUCTION The aim of this study was to determine the safety and therapeutic potential of L-carnitine and valproic acid ( VPA ) in infants with spinal muscular atrophy ( SMA ) . METHODS Our investigation was an open-label phase 2 multicenter trial of L-carnitine and VPA in infants with SMA type I with retrospective comparison to an untreated , matched cohort . Primary outcomes were : safety and adverse events ; secondary outcomes were survival , time to death/>16 hours/day of ventilator support ; motor outcomes ; and maximum ulnar compound motor action potential amplitude . RESULTS A total of 245 AEs were observed in 35 of the 37 treated subjects ( 95 % ) . Respiratory events accounted for 49 % of all adverse events , result ing in 14 deaths . Survival was not significantly different between treated and untreated cohorts . DISCUSSION This trial provides evidence that , in infants with SMA type I  , L-carnitine/VPA is ineffective at altering survival . The substantial proportion of infants reaching end-points within 6 months of enrollment underscores the urgent need for pre-symptomatic treatment in SMA type I. Muscle Nerve 57 : 193 - 199 , 2018 Background Valproic acid ( VPA ) has demonstrated potential as a therapeutic c and i date for spinal muscular atrophy ( SMA ) in vitro and in vivo . Methods Two cohorts of subjects were enrolled in the SMA CARNIVAL TRIAL , a non-ambulatory group of “ sitters ” ( cohort 1 ) and an ambulatory group of “ walkers ” ( cohort 2 ) . Here , we present results for cohort 1 : a multicenter phase II r and omized double-blind intention-to-treat protocol in non-ambulatory SMA subjects 2–8 years of age . Sixty-one subjects were r and omized 1∶1 to placebo or treatment for the first six months ; all received active treatment the subsequent six months . The primary outcome was change in the modified Hammersmith Functional Motor Scale ( MHFMS ) score following six months of treatment . Secondary outcomes included safety and adverse event data , and change in MHFMS score for twelve versus six months of active treatment , body composition , quantitative SMN mRNA levels , maximum ulnar CMAP amplitudes , myometry and PFT measures . Results At 6 months , there was no difference in change from the baseline MHFMS score between treatment and placebo groups ( difference = 0.643 , 95 % CI = −1.22–2.51 ) . Adverse events occurred in > 80 % of subjects and were more common in the treatment group . Excessive weight gain was the most frequent drug-related adverse event , and increased fat mass was negatively related to change in MHFMS values ( p = 0.0409 ) . Post-hoc analysis found that children ages two to three years that received 12 months treatment , when adjusted for baseline weight , had significantly improved MHFMS scores ( p = 0.03 ) compared to those who received placebo the first six months . A linear regression analysis limited to the influence of age demonstrates young age as a significant factor in improved MHFMS scores ( p = 0.007 ) . Conclusions This study demonstrated no benefit from six months treatment with VPA and L-carnitine in a young non-ambulatory cohort of subjects with SMA .  Weight gain , age and treatment duration were significant confounding variables that should be considered in the design of future trials . Trial Registry Clinical trials.gov 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 Background Spinal muscular atrophy ( SMA ) is an autosomal recessive disorder that affects the motoneurons of the spinal anterior horn , result ing in hypotonia and muscle weakness . The disease is caused by deletion or mutation in the telomeric copy of SMN gene ( SMN1 ) and clinical severity is in part determined by the copy number of the centromeric copy of the SMN gene ( SMN2 ) . The SMN2 mRNA lacks exon 7 , result ing in a production of lower amounts of the full-length SMN protein . Knowledge of the molecular mechanism of diseases has led to the discovery of drugs capable of increasing SMN protein level through activation of SMN2 gene . One of these drugs is the valproic acid ( VPA ) , a histone deacetylase inhibitor . Methods Twenty-two patients with type II and III SMA , aged between 2 and 18 years , were treated with VPA and were evaluated five times during a one-year period using the Manual Muscle Test ( Medical Research Council scale-MRC ) , the Hammersmith Functional Motor Scale ( HFMS ) , and the Barthel Index . Results After 12 months of therapy , the patients did not gain muscle strength . The group of children with SMA type II presented a significant gain in HFMS scores during the treatment . This improvement was not observed in the group of type III patients . The analysis of the HFMS scores during the treatment period in the groups of patients younger and older than 6 years of age did not show any significant result . There was an improvement of the daily activities at the end of the VPA treatment period . Conclusion Treatment of SMA patients with VPA may be a potential alternative to alleviate the progression of the disease . Trial Registration Clinical Trials.gov : Non-r and omised studies of the effects of interventions are critical to many areas of healthcare evaluation , but their results may be biased . It is therefore important to underst and and appraise their strengths and weaknesses . We developed ROBINS-I ( “ Risk Of Bias In Non-r and omised Studies - of Interventions ” ) , a new tool for evaluating risk of bias in estimates of the comparative effectiveness ( harm or benefit ) of interventions from studies that did not use r and omisation  to allocate units ( individuals or clusters of individuals ) to comparison groups . The tool will be particularly useful to those undertaking systematic review s that include non-r and omised studies Background Multiple lines of evidence have suggested that valproic acid ( VPA ) might benefit patients with spinal muscular atrophy ( SMA ) . The SMA CARNIVAL TRIAL was a two part prospect i ve trial to evaluate oral VPA and l-carnitine in SMA children . Part 1 targeted non-ambulatory children ages 2–8 in a 12 month cross over design . We report here Part 2 , a twelve month prospect i ve , open-label trial of VPA and L-carnitine in ambulatory SMA children . Methods This study involved 33 genetically proven type 3 SMA subjects ages 3–17 years . Subjects underwent two baseline assessment s over 4–6 weeks and then were placed on VPA and L-carnitine for 12 months . Assessment s were performed at baseline , 3 , 6 and 12 months . Primary outcomes included safety , adverse events and the change at 6 and 12 months in motor function assessed using the Modified Hammersmith Functional Motor Scale Extend ( MHFMS-Extend ) , timed motor tests and fine motor modules . Secondary outcomes included changes in ulnar compound muscle action potential amplitudes ( CMAP ) , h and held dynamometry , pulmonary function , and Pediatric Quality of Life Inventory scores . Results Twenty-eight subjects completed the study .  VPA and carnitine were generally well tolerated . Although adverse events occurred in 85 % of subjects , they were usually mild and transient . Weight gain of 20 % above body weight occurred in 17 % of subjects . There was no significant change in any primary outcome at six or 12 months . Some pulmonary function measures showed improvement at one year as expected with normal growth . CMAP significantly improved suggesting a modest biologic effect not clinical ly meaningful . Conclusions This study , coupled with the CARNIVAL Part 1 study , indicate that VPA is not effective in improving strength or function in SMA children . The outcomes used in this study are feasible and reliable , and can be employed in future trials in SMA . Trial Regsitration Clinical trials.gov Preliminary in vitro and in vivo studies with valproic acid ( VPA ) in cell lines and patients with spinal muscular atrophy ( SMA ) demonstrate increased expression of SMN , supporting the possibility of therapeutic benefit . We performed an open label trial of VPA in 42 subjects with SMA to assess safety and explore potential outcome measures to help guide design of future controlled clinical trials . Subjects included 2 SMA type I ages 2–3 years , 29 SMA type II ages 2–14 years and 11 type III ages 2–31 years , recruited from a natural history study .  VPA was well-tolerated and without evident hepatotoxicity . Carnitine depletion was frequent and temporally associated with increased weakness in two subjects . Exploratory outcome measures included assessment of gross motor function via the modified Hammersmith Functional Motor Scale ( MHFMS ) , electrophysiologic measures of innervation including maximum ulnar compound muscle action potential ( CMAP ) amplitudes and motor unit number estimation ( MUNE ) , body composition and bone density via dual-energy X-ray absorptiometry ( DEXA ) , and quantitative blood SMN mRNA levels . Clear decline in motor function occurred in several subjects in association with weight gain ; mean fat mass increased without a corresponding increase in lean mass . We observed an increased mean score on the MHFMS scale in 27 subjects with SMA type II ( p≤0.001 ) ; however , significant improvement was almost entirely restricted to participants < 5 years of age . Full length SMN levels were unchanged and Δ7SMN levels were significantly reduced for 2 of 3 treatment visits . In contrast , bone mineral density ( p≤0.0036 ) and maximum ulnar CMAP scores ( p≤0.0001 ) increased significantly . Conclusions While VPA appears safe and well-tolerated in this initial pilot trial , these data suggest that weight gain and carnitine depletion are likely to be significant confounding factors in clinical trials . This study highlights potential strengths and limitations of various c and i date outcome measures and underscores the need for additional controlled clinical trials with VPA targeting more restricted cohorts of subjects . Trial Registration Clinical Abstract Background : Clinical trials of therapies for spinal muscular atrophy ( SMA ) that are design ed to increase the expression the SMN protein ideally include careful assessment of relevant SMN biomarkers . Objective : In the SMA VALIANT trial , a recent double-blind placebo-controlled crossover study of valproic acid ( VPA ) in ambulatory adult subjects with SMA , we investigated relevant pharmacodynamic biomarkers in blood sample s from SMA subjects by direct longitudinal measurement of histone acetylation and SMN mRNA and protein levels in the presence and absence of VPA treatment . Methods : Thirty-three subjects were r and omized to either VPA or placebo for the first 6 months followed by crossover to the opposite arm for an additional 6 months . Outcome measures were compared between the two treatments ( VPA and placebo ) using a st and ard crossover analysis . Results : A significant increase in histone H4 acetylation was observed with VPA treatment ( p = 0.005 ) . There was insufficient evidence to suggest a treatment effect with either full length or truncated SMN mRNA transcript levels or SMN protein levels . Conclusions : These measures were consistent with the observed lack of change in the primary clinical outcome measure in the VALIANT trial . These results also highlight the added benefit of molecular and pharmacodynamic biomarker measurements in the interpretation of clinical trial outcomes INTRODUCTION An open-label trial suggested that valproic acid ( VPA ) improved strength in adults with spinal muscular atrophy ( SMA ) . We report a 12-month , double-blind , cross-over study of VPA in ambulatory SMA adults . METHODS There were 33 subjects , aged 20–55 years , included in this investigation . After baseline assessment , subjects were r and omized to receive VPA ( 10–20 mg/kg/day ) or placebo . At 6 months , patients were switched to the other group . Assessment s were performed at 3 , 6 , and 12 months . The primary outcome was the 6-month change in maximum voluntary isometric contraction testing with pulmonary , electrophysiological , and functional secondary outcomes . RESULTS Thirty subjects completed the study .  VPA was well tolerated , and compliance was good . There was no change in primary or secondary outcomes at 6 or 12 months . CONCLUSIONS VPA did not improve strength or function in SMA adults . The outcomes used are feasible and reliable and can be employed in future trials in SMA adults Spinal muscular atrophy results from loss of the survival motor neuron 1 ( SMN1 ) gene and malfunction of the remaining SMN2 . We investigated whether valproic acid can elevate human SMN expression in vivo BACKGROUND Nusinersen is a 2'-O-methoxyethyl phosphorothioate-modified antisense drug being developed to treat spinal muscular atrophy .  Nusinersen is specifically design ed to alter splicing of SMN2 pre-mRNA and thus increase the amount of functional survival motor neuron ( SMN ) protein that is deficient in patients with spinal muscular atrophy . METHODS This open-label , phase 2 , escalating dose clinical study assessed the safety and tolerability , pharmacokinetics , and clinical efficacy of multiple intrathecal doses of nusinersen ( 6 mg and 12 mg dose equivalents ) in patients with infantile-onset spinal muscular atrophy . Eligible participants were of either gender aged between 3 weeks and 7 months old with onset of spinal muscular atrophy symptoms between 3 weeks and 6 months , who had SMN1 homozygous 
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Qualitative synthesis showed that other motor functions were not improved , while respiratory function test results were contradictory .
Moreover , most of the included studies reported no serious AEs related to VPA use , although weight gain , gastrointestinal symptoms and respiratory symptoms were notable problems .
Conclusions Our study suggests that VPA treatment results in an improvement in gross motor functions for SMA patients , but not in other assessment s of motor function or , possibly , in respiratory function .
Furthermore , VPA appears to be a relatively safe drug , although treatment may be associated with a wide range of AEs ( including body weight increase , fatigue , fever , flu-like symptoms , irritability , and pain ) .