Drug treatment for spinal muscular atrophy type I (Review)

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1 Wadman RI, Bosboom WMJ, van der Pol WL, van den Berg LH, Wokke JHJ, Iannaccone ST, Vrancken AFJE This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2012, Issue 4

2 T A B L E O F C O N T E N T S HEADER ABSTRACT PLAIN LANGUAGE SUMMARY BACKGROUND OBJECTIVES METHODS RESULTS Figure DISCUSSION AUTHORS CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES CHARACTERISTICS OF STUDIES DATA AND ANALYSES ADDITIONAL TABLES APPENDICES WHAT S NEW HISTORY CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST SOURCES OF SUPPORT DIFFERENCES BETWEEN PROTOCOL AND REVIEW INDEX TERMS i

3 [Intervention Review] Drug treatment for spinal muscular atrophy type I Renske I Wadman 1, Wendy MJ Bosboom 2, W Ludo van der Pol 1, Leonard H van den Berg 1, John HJ Wokke 1, Susan T Iannaccone 3, Alexander FJE Vrancken 1 1 Department of Neurology, University Medical Center Utrecht, Utrecht, Netherlands. 2 Department of Neurology, Sint Lucas Andreas Hospital, Amsterdam, Netherlands. 3 Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA Contact address: Renske I Wadman, Department of Neurology, University Medical Center Utrecht, Rudolf Magnus Institute for Neuroscience, Universiteitsweg 100, Utrecht, 3584 CG, Netherlands. Editorial group: Cochrane Neuromuscular Disease Group. Publication status and date: Edited (no change to conclusions), published in Issue 4, Review content assessed as up-to-date: 8 March Citation: Wadman RI, Bosboom WMJ, van der Pol WL, van den Berg LH, Wokke JHJ, Iannaccone ST, Vrancken AFJE. Drug treatment for spinal muscular atrophy type I. Cochrane Database of Systematic Reviews 2012, Issue 4. Art. No.: CD DOI: / CD pub4. Background A B S T R A C T Spinal muscular atrophy (SMA) is caused by degeneration of anterior horn cells of the spinal cord, which leads to progressive muscle weakness. Children with SMA type I will never be able to sit without support and usually die by the age of two years. There are no known efficacious drug treatments that influence the course of the disease. This is an update of a review first published in Objectives To evaluate whether drug treatment is able to slow or arrest the disease progression of SMA type I, and to assess if such therapy can be given safely. Drug treatment for SMA types II and III is the topic of a separate updated Cochrane review. Search methods We searched the Cochrane Neuromuscular Disease Group Specialized Register (8 March 2011), CENTRAL (The Cochrane Library 2011, Issue 1), MEDLINE (January 1991 to February 2011), EMBASE (January 1991 to February 2011) and ISI Web of Knowledge (January 1991 to 8 March 2011). We searched the Clinical Trials Registry of the U.S. National Institute of Health (www.clinicaltrials.gov) (8 March 2011) to identify additional trials that had not yet been published. Selection criteria We sought all randomised or quasi-randomised trials that examined the efficacy of drug treatment for SMA type I. Participants had to fulfil the clinical criteria and have a deletion or mutation of the SMN1 gene (5q ) confirmed by genetic analysis. The primary outcome measure was time from birth until death or full time ventilation. Secondary outcome measures were development of rolling, sitting or standing within one year after the onset of treatment, and adverse events attributable to treatment during the trial period. Data collection and analysis Two authors (RW and AV) independently reviewed and extracted data from all potentially relevant trials. For included studies, pooled relative risks and standardised mean differences were to be calculated to assess treatment efficacy. 1

4 Main results One small randomised controlled study comparing riluzole treatment to placebo for 10 SMA type 1 children was identified and included in the original review. No further trials were identified for the update in Regarding the primary outcome measure, three of seven children treated with riluzole were still alive at the ages of 30, 48 and 64 months, whereas all three children in the placebo group died; but the difference was not statistically significant. Regarding the secondary outcome measures, none of the children in the riluzole or placebo group developed the ability to roll, sit or stand, and no adverse effects were observed. For several reasons the overall quality of the study was low, mainly because the study was too small to detect an effect and because of baseline differences. Follow-up of the 10 included children was complete. Authors conclusions No drug treatment for SMA type I has been proven to have significant efficacy. P L A I N L A N G U A G E S U M M A R Y Drug treatment for spinal muscular atrophy type I Spinal muscular atrophy (SMA) is a severe neuromuscular disease with onset in childhood and adolescence that results in progressive muscle weakness. There are three main types of SMA. Drug treatment for SMA types II and III is discussed in a separate Cochrane review. The age of onset of SMA type I, also known as Werdnig-Hoffmann disease, is before six months. Children with SMA type I will never be able to sit without support and usually die by the age of two years. It is one of the most important causes of death due to a genetic disease in childhood. There was only one small randomised trial in the original review, which assessed the efficacy of riluzole for 10 children with SMA type I. In this trial all three children in the placebo group died, but three of the seven children treated with riluzole were still alive at the ages of 30, 48 and 64 months. However, none of the children in the riluzole or placebo group developed the ability to roll, sit or stand. For several reasons the overall quality of the study was low, mainly because the study was too small to detect an effect and there were baseline differences that resulted in risk of bias. Evidence is insufficient to recommend riluzole for SMA type I. No further trials were identified for this 2011 update. No drug treatment has been shown to have significant efficacy for SMA type I. B A C K G R O U N D Spinal muscular atrophy (SMA) is a neuromuscular disorder of childhood and adolescence with an annual incidence of 1 in 6000 to 10,000 (Cobben 2001; Nicole 2002). It is caused by degeneration of anterior horn cells and is clinically manifested by progressive muscle weakness (Talbot 1999; Iannaccone 2001). Other parts of the peripheral nervous system such as the neuromuscular junction, and possibly the muscle, may also be affected by disruption in maturation and development, which is probably secondary to the deficiency of survival motor neuron (SMN) protein (Braun 1995; Cifuentes-Diaz 2002; Kariya 2008; Murray 2008). The typical pattern of muscle weakness in SMA is weakness of the limbs, which is proximal more than distal, with the lower limbs involved earlier than the upper limbs (Thomas 1994; Kroksmark 2001). Intercostal muscles also become involved but usually sparing the diaphragm. Survival depends primarily on respiratory function and not necessarily on motor ability (Russman 1992; Dubowitz 1995; Talbot 1999). There is often a fine tremor in the fingers (Iannaccone 1998). Although the face is often spared, tongue fasciculations and facial weakness are not unusual findings (Iannaccone 1993). The cognitive function of SMA patients is normal and, at the end of the disease course, there is often a striking discrepancy between alertness and the ability to move (Thomas 1994; Iannaccone 1998). There is denervation and reinnervation on electrophysiological examination (Iannaccone 1998; Nicole 2002). There are three main types of SMA (Munsat 1991; Munsat 1992; Zerres 1999; Bertini 2005). SMA type I is the most common form, and is also known as Werdnig-Hoffmann disease, acute SMA and infantile-onset SMA. The age of onset is before six months. Children with SMA type I will never be able to sit without support and usually (without 2

5 intensive supportive care) die by the age of two years (Iannaccone 1993; Thomas 1994; Cobben 2008). It is characterised by severe progressive muscle weakness and hypotonia (Iannaccone 1998). It is one of the most important causes of death due to a genetic disease in childhood (Nicole 2002). SMA type II is the intermediate type and is also known as intermediate SMA, juvenile SMA and chronic SMA. The age of onset is between six and 18 months. Children with SMA type II develop the ability to sit independently but never become able to walk without support. They often develop severe pulmonary and orthopaedic complications (Bertini 2005). The children survive beyond two years and may live into adolescence or longer (Russman 1996; Zerres 1997). SMA type III is known as Kugelberg-Welander disease, Wohlfart- Kugelberg-Welander disease, and mild SMA. The age of onset is after 18 months. Children with SMA type III develop the ability to walk at some time, although many will lose this ability again around puberty. Life expectancy may be normal (Russman 1992; Zerres 1997). Classification of SMA according to the International SMA Collaboration is based on age of onset, maximal achieved motor function and age of death (Munsat 1991; Munsat 1992). Although there are different subtypes, SMA has a broad clinical spectrum. There is overlap between subtypes; there are, for instance, children with SMA who are without the ability to sit but have a relatively long survival time (Thomas 1994; Zerres 1995). There are children with SMA I who develop head control and other children with a chronic evolution from the onset. There are children with SMA with disease onset before six months and the ability to sit, and others with disease onset before 18 months and the ability to walk (Russman 1992; Zerres 1995). The maximum function achieved predicts the natural course of the disease better than the age of onset (Zerres 1995; Russman 1996). A very severe type of SMA has been described with onset before birth and death within a few months, known as SMA type 0 or congenital SMA (Dubowitz 1999; Zerres 1999). At the other end of the spectrum, a rare adult form of SMA, known as SMA type IV, has an age of onset after 35 years (Zerres 1995; Cobben 2001). SMA (type 0 to IV) is an autosomal recessive disease and these types of the disease have been mapped to chromosome 5q (Brzustowicz 1990; Gilliam 1990; Melki 1990a; Melki 1990b; Lefebvre 1995). This chromosomal region contains a duplicate SMN gene, the telomeric SMN gene (SMN1 or SMNt) and the centromeric SMN gene (SMN2 or SMNc) (Iannaccone 1998; Nicole 2002). The product of the SMN gene is the SMN protein. The SMN1 gene is transcribed into a full-length form, which results in a large amount of stable SMN protein. The SMN2 gene is transcribed into a truncated form lacking exon 7 (90%), which results in an unstable SMN protein without function, and to a lesser extent into a full-length form (10%), which results in a small amount of stable SMN protein (Lorson 1999; Cartegni 2006). In SMA, the SMN1 gene is deleted or mutated in 95% to 99% of the patients (Lefebvre 1995; Wirth 2000). Consequently, there is no transcription of stable SMN protein from the SMN1 gene and the SMN2 gene is not able to produce enough stable SMN protein (Cobben 1995; Lefebvre 1995; Nicole 2002). The clinical severity of the disease depends on the amount of SMN protein (Lefebvre 1997; Parsons 1998; Jablonka 2000; Veldink 2001) and this is related to the number of copies of the SMN2 gene (Feldkotter 2002; Harada 2002; Swoboda 2005; Piepers 2008b). Approximately two copies of the SMN2 gene (± 20% stable SMN protein) very frequently produce SMA type I, three copies (± 30% stable SMN protein) mostly produce SMA type II, and four copies (± 40% stable SMN protein) of the SMN2 gene produce SMA type III and type IV (Melki 1994; Parsons 1998; Cobben 2001; Wirth 2006c; Piepers 2008b). The exact cellular function of the SMN protein is not known (Sumner 2007). In motor neurons the mrna splicing is probably dependent on the abundance of SMN protein (Lefebvre 1998; Pellizzoni 1998; Gendron 1999; Jablonka 2000). SMN protein might be necessary for motor axon outgrowth (McWhorter 2003), or SMN might have a protecting role in motor neurons against superoxide dismutase 1 (SOD1) toxicity (Zou 2007). However, reduced amounts of functional SMN protein are found in all cell types of patients with SMA. The reason why abnormalities cause dysfunction of motor neurons and not other cell types remains to be established (Talbot 1999; Merlini 2002; Nicole 2002). Other hypotheses regarding the pathogenesis of SMA include defective inhibition of apoptosis, glutamate excitotoxicity, oxidative stress, defective axonogenesis and lack of neurotrophic factors in nerve or muscle (Takeuchi 1994; Greensmith 1995; Crawford 1996; Talbot 1999; Zerres 1999; Miller 2001; Merlini 2002; Merlini 2003; Russman 2003; Oprea 2008; Parker 2008). Administration of agents capable of increasing the expression of SMN protein levels may improve the outcome in SMA (Lorson 1998; Feldkotter 2002; Gavrilina 2008). Transcriptional SMN2 activation, facilitation of correct SMN2 splicing, translational activation and stabilisation of the full length SMN protein are considered as strategies for SMA therapy. Other strategies for therapy are improvement of motor neuron viability by neuroprotecting or neurotrophic agents (Wirth 2006b; Lunn 2008; Thurmond 2008). Recently, gene conversion from SMN2 gene to SMN1 gene in human cells from SMA patients has been reported (DiMatteo 2008). In the future stem, cell therapy or gene therapy may compensate for the lack of sufficient SMN protein (Bertini 2005; Wirth 2006a; Lunn 2008). There is no known efficacious drug treatment for SMA type I or SMA types II and III (Merlini 2002; Nicole 2002; Iannaccone 2003). Management consists of preventing or treating the complications (Iannaccone 1998; Russman 2003; Wang 2007). This is 3

6 an update of a review first published in Drug treatment for SMA types II and III is the subject of a separate Cochrane review (Wadman 2011). O B J E C T I V E S To systematically review the evidence from randomised controlled trials concerning the efficacy and safety of any drug therapy designed to slow or arrest disease progression of SMA type I. 4. Adverse effects attributable to treatment during the whole study period, separated into severe (requiring or lengthening hospitalisation, life threatening or fatal) and others. In the future we will include a summary of findings table. The table will give a quick overview of time from birth till death or ventilation, outcome measures in clinical scores and number and type of (serious) adverse events. Search methods for identification of studies M E T H O D S Criteria for considering studies for this review Types of studies All randomised or quasi-randomised (alternate or other systematic treatment allocation) studies examining the effect of drug treatment designed to slow or arrest disease progression in children with SMA type I. Types of participants Children with SMA type I fulfilling the criteria outlined in Table 1. Types of interventions Any drug treatment, alone or in combination, designed to slow or arrest the progress of the disease compared to placebo, with no restrictions on the route of administration. Types of outcome measures Electronic searches We searched the Cochrane Neuromuscular Disease Group Specialized Register (8 March 2011), CENTRAL (The Cochrane Library 2011, Issue 1), MEDLINE (January 1991 to February 2011), EM- BASE (January 1991 to February 2011) and ISI Web of Knowledge (from January 1991 to 8 March 2011). Searches were performed from 1991 onwards because at that time genetic analysis of the SMN1 gene became widely available and could establish the diagnosis of SMA. We consulted the clinical trials registry of the U.S. National Institute of Health (www.clinicaltrials.gov) (8 March 2011) to identify additional trials that had not yet been published. For the search strategies see: Appendix 1 (MEDLINE), Appendix 2 (EMBASE), Appendix 3 (CENTRAL), Appendix 4 (ISI Web of Knowledge) and Appendix 5 (clinical trials registry). Searching other resources We handsearched relevant cited references, published studies, reviews, textbooks and conference proceedings. Readers are invited to suggest studies, particularly in other languages, which should be considered for inclusion. Primary outcomes Time from birth until death or full time ventilation (a requirement for 16 hours of ventilation out of 24 hours regardless of whether this is with a tracheostomy, tube or mask). Secondary outcomes 1. Development of rolling within one year after the onset of treatment. 2. Development of sitting within one year after the onset of treatment. 3. Development of standing within one year after the onset of treatment. Data collection and analysis Selecting trials for inclusion For this updated review, two authors (RW and AV) independently checked titles and abstracts obtained from the literature searches to identify potentially relevant trials for full review. From the full texts, the authors independently selected the trials that met the selection criteria for inclusion and graded their risk of bias. Authors were not blinded to the trial author and source institution. The authors resolved disagreement by reaching consensus. 4

7 Assessment of methodological quality The methodological quality assessment took into account allocation concealment, security of randomisation, intention-to-treat analysis, participant blinding (parent blinding), observer blinding, explicit inclusion and exclusion criteria, explicit outcome criteria and how studies dealt with baseline differences between treatment groups. Each item was scored according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). Risk of bias was graded as high, low or unclear. Two authors (RW and AV) graded the risk of bias independently. In the case of disagreement, the authors reassessed the studies and reached agreement by consensus. Methods used to collect data from included trials Two authors (RW and AV) extracted data independently using a specially designed data extraction form. We obtained missing data from the trial authors whenever possible. Disagreement did not occur, but would have been resolved by consensus with third party adjudication if necessary. Statistical analysis Only results of studies with the same class of drug treatment were to be pooled. For dichotomous data we would have calculated the relative risk for each study. To assess overall efficacy from all the studies, we would have calculated pooled relative risk estimates. If Chi 2 analysis had shown the data to be heterogeneous, we would have used a random-effects model with maximum likelihood estimation. If no heterogeneity was demonstrated, we would have used a fixed-effect model (Mantel-Haenszel risk ratio (RR) method). For continuous data, we would have calculated mean differences between therapy and no therapy for each study. Mean differences (MD) were to be calculated if data were sufficiently comparable between studies; if not, we would have applied standard Review Manager (RevMan) generic inverse variance (GIV) analysis using treatment effect differences with their standard errors. Statistical uncertainty would have been expressed with 95% confidence intervals. Where studies had different follow-up periods appropriate adjustments would have been used, possibly with the RevMan GIV facility or, if necessary, Poisson regression allowing for the aggregate person time at risk in the study groups. For survival or time to full time ventilation we would have expected to obtain results from Kaplan-Meier survival analysis. A sensitivity analysis would have been performed on the basis of the methodological quality of the studies. Statistical considerations would have involved a trade-off between bias and precision. Risk of bias will be assessed as unclear when too few details are available to make a judgement of high or low risk; when the risk of bias is genuinely unknown despite sufficient information about the conduct; or when an entry is not relevant to a study. All studies will be described by a precise risk of bias. Formal comparisons of intervention effects according to risk of bias would be done using meta- regression. The major approach to incorporating risk of bias assessments would be to incorporate and restrict meta-analyses to studies at low (or lower) risk of bias. In the Discussion section, we have reviewed the data from open and uncontrolled studies. In addition, adverse events found in this review are discussed in relation to the side effects of the drugs reported in the nonrandomised literature. The ethical dimensions of the disease and its treatment are also discussed. R E S U L T S Description of studies See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies. For this updated review the number of studies found by the new, current search strategies were: MEDLINE 317 (85 new), EM- BASE 89 (22 new), Cochrane Neuromuscular Disease Specialized Register 30 (6 new), Cochrane Central Register of Controlled Trials (CENTRAL) 52 (11 new) and ISI Web of Knowledge 418 (23 new). We identified and assessed five studies (one new) for possible inclusion in the review. Four studies were excluded because they were not randomised or controlled, or clinical outcome measures were not assessed (Franz 1995; Chang 2002; Brichta 2006; Swoboda 2009). See Characteristics of excluded studies. One study remained that fulfilled the selection criteria. This study was a randomised placebo-controlled study of riluzole in children with SMA type I (Russman 2003). Details of the study are shown in Characteristics of included studies. The main outcome measure of the study was the occurrence of adverse events, the secondary outcome was mortality under the assumption that the life expectancy would be no more than 24 months. All children fulfilled clinical criteria for SMA type I, namely onset before the age of six months, never achieving the ability to sit independently and genetic confirmation of the diagnosis of SMA. The study investigators planned to include 30 children with randomisation in a 2:1 ratio (riluzole: placebo). Unfortunately, support from the pharmaceutical industry was withdrawn when Rhone-Poulenc was taken over by Aventis. From then on no more children were enrolled in the study and therefore the total number of included children was only 10. Risk of bias in included studies The Risk of bias assessments for the included study (Russman 2003) can be seen in Characteristics of included studies and Figure 1. For several reasons the overall quality of the study was low. Only one-third of the intended enrolment was reached and there were 5

8 baseline differences between the treatment groups that may have influenced the results: in the placebo group, the age at onset of symptoms, age at diagnosis and age at enrolment in the study were younger than in the riluzole group. The randomisation method and blinding of parents and observers were not clear. Allocation concealment and diagnostic criteria for SMA type I were adequate. The primary outcome was clear and follow-up of the 10 included children was complete. Figure 1. Risk of bias summary: review authors judgements about each risk of bias item for each included study. Effects of interventions We could not perform a meta-analysis because only one study was included (Russman 2003). For this study statistical analysis was not performed because only 10 children of the intended 30 participants were enrolled before funding was withdrawn. Therefore the results (see Table 2 Outcomes of included study ) are only a description of the data from this study. Primary outcome measure Time from birth until death or full time ventilation In the group treated with riluzole, four of seven (57%) children died at a median age of 17 (range 5 to 25) months. In the placebo group all three (100%) children died at a median age of 8 (range 6

9 6 to 13) months. Three children treated with riluzole were still alive at the age of 30, 48 and 64 months, which was 23, 39 and 49 months after starting the therapy. These children used bilevel positive airway pressure ventilation (BiPAP) only at night. Secondary outcome measures Development of rolling, sitting or standing within one year after the onset of treatment None of the children in the riluzole or placebo group developed the ability to roll, sit or stand. Adverse side effects, separated into severe and others There were no adverse side effects in either the riluzole or the placebo-treated group. D I S C U S S I O N In SMA type I there was only one randomised controlled study (RCT) on drug treatment (Russman 2003). This study compared treatment with riluzole versus placebo (Table 2). Riluzole is thought to have a neuroprotective effect on the motor neuron by blocking the presynaptic release of glutamate. Glutamate is released after presynaptic depolarisation and if the amino acid is not efficiently cleared it leads to increased levels of free radicals and eventually degeneration of motor neurons (Bryson 1996; Merlini 2003). Riluzole has been proven to be modestly effective in slowing disease progression in amyotrophic lateral sclerosis (ALS, motor neuron disease) (Bensimon 1994; Lacomblez 1996; Miller 1996a; Riviere 1998; Traynor 2003; Miller 2007) with only minimal adverse effects (Wokke 1996). In a mouse model of SMA riluzole attenuated the disease progression (Haddad 2003). In the included trial (Russman 2003), three children treated with riluzole were still alive at the ages of 30, 48 and 64 months, whereas in the placebo group all children died. It is not possible to conclude from this trial that riluzole is an efficacious treatment in SMA type I because the study did not have enough power due to the fact that support from the pharmaceutical industry was withdrawn and only 10 children were randomised in a 2:1 ratio. Also, the children in the placebo group were younger at the onset of symptoms, at diagnosis and at enrolment in the study compared to the children treated with riluzole. These baseline differences could imply that the placebo group was a subgroup of SMA type I with a worse disease course than the other children with SMA type I. However, it is intriguing that three out of seven children treated with riluzole were still alive at ages two, three and five years and used BiPAP ventilation support only at night. According to the clinical criteria for SMA type I they should have died before the age of two years. Children with a diagnosis of SMA type I who survive longer than two years may be considered to have SMA type II, but the children in this study did not achieve the ability to sit and therefore did not fulfil the clinical criteria for SMA type II. Although the study had insufficient power and the treatment groups were not comparable at baseline, riluzole treatment in SMA type I appears to be safe and well tolerated. A larger trial with riluzole is needed to evaluate to what extent treatment with this drug could be efficacious. Other drugs that have been tested in open and uncontrolled studies of children with SMA type I are valproate, hydroxyurea and recombinant human ciliary neurotrophic factor (CNTF) (Franz 1995; Chang 2002; Brichta 2006; Swoboda 2009). However, one trial with valproate studied human SMN expression in blood, not the disease course (Brichta 2006). A multicentre phase I/II trial on treatment with valproate and carnitine of infants with SMA type I is ongoing, but this is an open uncontrolled study (NCT ). In amyotrophic lateral sclerosis (ALS), a fatal disease of the motor neurons, there was no effect on disease course in a randomised placebo-controlled trial of valproate in 163 participants (Piepers 2008a). The study with hydroxyurea in two participants with SMA type I, five participants with SMA type II and two participants with SMA type III demonstrated an improvement in muscle power and clinical improvement without side effects (Chang 2002). A phase I/II trial using hydroxyurea in children with SMA type I has been completed, but the results have not yet been published (NCT ). An RCT on hydroxyurea in participants with SMA types II and III did not show any effect (Chen 2010). There are no trials on the effect of treatment with hydroxyurea in other neuromuscular diseases. A nonrandomised uncontrolled study on the safety and tolerability of recombinant ciliary neurotrophic factor (CNTF) included 10 children with SMA type I (Franz 1995). Six children died; no change in muscle function and strength was noted and no differences could be made between disease course and side effects. Two randomised placebo-controlled trials of CNTF in 570 and 730 patients with ALS, and a meta-analysis, were negative (ACTS 1996; Miller 1996b; Bongioanni 2004). A multicenter, open label phase I/II trial on treatment with multiple dosage levels of phenylbutyrate to determine the maximum tolerated dose (MTD) or the highest dose that can be safely given to children with SMA type I has been terminated due to extremely slow enrolment (NCT ). A similar trial with increasing dose of sodium butyrate in children with SMA types II and III also has been terminated because of poor compliance with the study drug administration (NCT ). There is an ongoing phase I/II study with phenylbutyrate in presymptomatic infants genetically confirmed to have SMA and to have probable SMA type I or type II (NCT ). From these studies it is not possible to conclude whether treatment 7

10 with the drugs used could have a beneficial clinical effect on the disease course of SMA type I. Other drugs that seem promising in open and uncontrolled trials in children and adults with SMA types II and III are described in the separate Cochrane review on drug treatment for spinal muscular atrophy type II and III (Wadman 2011). It is ethically debatable whether it is desirable to treat children with SMA type I with a drug that has an effect on survival but not on achieving motor milestones such as rolling, sitting, standing or walking. Recently, arguments for and against were described (Bach 2008; Ryan 2008). In our opinion children with SMA type I should not be treated with a drug that may prolong survival but does not appear to improve motor function. Therefore, we would not recommend treatment of children with SMA type I with riluzole. There is a broad range of practice regarding pulmonary, nutritional, orthopaedic, and other forms of supportive therapy (Wang 2007) in children with SMA type I. Practice guidelines for the clinical care of children and adults with SMA are given in the consensus statement for standard care in SMA (Wang 2007). Due to intensive supportive care, such as ventilation, mechanical insufflation-exsufflation and gastronomy tube feeding, the survival of children with SMA type I has significantly increased in recent years (Oskoui 2007). For future trials it is very important that the supportive care in the different treatment arms is the same. If some children are treated with pro-active care and others with palliative care, stratifying these two groups in each treatment arm (drug or placebo) should be considered. A U T H O R S C O N C L U S I O N S Implications for practice No drug treatment has been shown to have significant efficacy for SMA type I. Implications for research Possible drug treatments for SMA type I should be sought and large randomised placebo-controlled studies are needed to show the efficacy of drug treatment. A larger trial with riluzole is needed to evaluate to what extent this drug could be efficacious. Future trials should report possible side effects, especially serious adverse events. The time from the beginning of treatment until death or full time ventilation should be the primary outcome measure. The (intensive) supportive care in each treatment arm should be the same. The change in motor function, daily functioning and quality of life should also be considered as outcome measures. Developing a new functional rating scale or choosing an existing functional rating scale as a standard scale for all trials is recommended. Study investigators in multicenter trials should be well trained to reliably and consistently measure muscle strength by quantitative myometry and pulmonary function to avoid large variation in the measurements between and within the participating centres. A C K N O W L E D G E M E N T S Editorial support for the original review for the Cochrane Neuromuscular Disease Group was funded by the TREAT NMD European Union Grant The Cochrane Neuromuscular Disease Group editorial base is supported by the MRC Centre for Neuromuscular Disease and the Muscular Dystrophy Campaign. R E F E R E N C E S References to studies included in this review Russman 2003 {published data only} Russman BS, Iannaccone ST, Samaha FJ. A phase 1 trial of riluzole in spinal muscular atrophy. Archives of Neurology 2003;60(11): [PUBMED: ] References to studies excluded from this review Brichta 2006 {published data only} Brichta L, Holker I, Haug K, Klockgether T, Wirth B. In vivo activation of SMN in spinal muscular atrophy carriers and patients treated with valproate. Annals of Neurology 2006;59(6): Chang 2002 {published data only} Chang JG, Tsai FJ, Wang WY, Jong YJ. Treatment of spinal muscular atrophy by hydroxyurea. American Journal of Human Genetics ; Vol. 71 Suppl, issue 4:2402. Franz 1995 {published data only} Franz DN, Tudor CA, Samaha FJ. A phase I trial of recombinant human ciliary neurotrophic factor in spinal muscular atrophy. Annals of Neurology ; Vol. 38, issue 3:546. Swoboda 2009 {published data only} Swoboda KJ, Scott CB, Reyna SP, Prior TW, LaSalle B, Sorenson SL, et al.phase II open label study of valproic acid in spinal muscular atrophy. PLoS One 2009;4(5):e5268. [PUBMED: ] References to ongoing studies NCT {published data only} NCT A pilot therapeutic trial using hydroxyurea in type I spinal muscular atrophy patients. (accessed 8 August 2011). 8

11 Additional references ACTS 1996 A double-blind placebo-controlled clinical trial of subcutaneous recombinant human ciliary neurotrophic factor (rhcntf) in amyotrophic lateral sclerosis. ALS CNTF Treatment Study Group. Neurology 1996;46(5): Bach 2008 Bach JR. The use of mechanical ventilation is appropriate in children with genetically proven spinal muscular atrophy type 1: the motion for. Paediatric Respiratory Reviews 2008; 9(1): Bensimon 1994 Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. New England Journal of Medicine 1994;330 (9): Bertini 2005 Bertini E, Burghes A, Bushby K, Estournet-Mathiaud B, Finkel RS, Hughes RA, et al.134th ENMC International Workshop: Outcome Measures and Treatment of Spinal Muscular Atrophy, February 2005, Naarden, The Netherlands. Neuromuscular Disorders 2005;15(11): Bongioanni 2004 Bongioanni P, Reali C, Sogos V. Ciliary neurotrophic factor (CNTF) for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database of Systematic Reviews 2004, Issue 3. [DOI: / CD pub2] Braun 1995 Braun S, Croizat B, Lagrange MC, Warter JM, Poindron P. Constitutive muscular abnormalities in culture in spinal muscular atrophy. Lancet 1995;345(8951): [PUBMED: ] Bryson 1996 Bryson HM, Fulton B, Benfield P. Riluzole. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in amyotrophic lateral sclerosis. Drugs 1996;52(4): Brzustowicz 1990 Brzustowicz LM, Lehner T, Castilla LH, Penchaszadeh GK, Wilhelmsen KC, Daniels R, et al.genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q Nature 1990;344(6266): Cartegni 2006 Cartegni L, Hastings ML, Calarco JA, de Stanchina E, Krainer AR. Determinants of exon 7 splicing in the spinal muscular atrophy genes, SMN1 and SMN2. American Journal of Human Genetics 2006;78(1): Chen 2010 Chen TH, Chang JG, Yang YH, Mai HH, Liang WC, Wu YC, et al.randomized, double-blind, placebo-controlled trial of hydroxyurea in spinal muscular atrophy. Neurology 2010;75(24): [PUBMED: ] Cifuentes-Diaz 2002 Cifuentes-Diaz C, Frugier T, Melki J. Spinal muscular atrophy. Seminars in Pediatric Neurology 2002;9(2): [PUBMED: ] Cobben 1995 Cobben JM, van der Steege, Grootscholten P, de Visser M, Scheffer H, Buys CH. Deletions of the survival motor neuron gene in unaffected siblings of patients with spinal muscular atrophy. American Journal of Human Genetics 1995;57(4): Cobben 2001 Cobben JM, de Visser M, Scheffer H. [From gene to disease; survival motor neuron protein and hereditary proximal spinal muscle atrophy]. Nederlands Tijdschrift voor Geneeskunde 2001;145(52): Cobben 2008 Cobben JM, Lemmink HH, Snoeck I, Barth PA, van der Lee JH, de Visser M. Survival in SMA type I: a prospective analysis of 34 consecutive cases. Neuromuscular Disorders 2008;18(7): Crawford 1996 Crawford TO, Pardo CA. The neurobiology of childhood spinal muscular atrophy. Neurobiology of Disease 1996;3(2): DiMatteo 2008 DiMatteo D, Callahan S, Kmiec EB. Genetic conversion of an SMN2 gene to SMN1: a novel approach to the treatment of spinal muscular atrophy. Experimental Cell Research 2008;314(4): Dubowitz 1995 Dubowitz V. Chaos in the classification of SMA: a possible resolution. Neuromuscular Disorders 1995;5(1):3 5. Dubowitz 1999 Dubowitz V. Very severe spinal muscular atrophy (SMA type 0): an expanding clinical phenotype. European Journal of Paediatric Neurology 1999;3(2): Feldkotter 2002 Feldkotter M, Schwarzer V, Wirth R, Wienker TF, Wirth B. Quantitative analyses of SMN1 and SMN2 based on real-time lightcycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy. American Journal of Human Genetics 2002;70(2): Gavrilina 2008 Gavrilina TO, McGovern VL, Workman E, Crawford TO, Gogliotti RG, DiDonato CJ, et al.neuronal SMN expression corrects spinal muscular atrophy in severe SMA mice while muscle-specific SMN expression has no phenotypic effect. Human Molecular Genetics 2008;17(8): Gendron 1999 Gendron NH, MacKenzie AE. Spinal muscular atrophy: molecular pathophysiology. Current Opinion in Neurology 1999;12(2): Gilliam 1990 Gilliam TC, Brzustowicz LM, Castilla LH, Lehner T, Penchaszadeh GK, Daniels RJ, et al.genetic homogeneity 9

12 between acute and chronic forms of spinal muscular atrophy. Nature 1990;345(6278): Greensmith 1995 Greensmith L, Vrbova G. Possible strategies for treatment of SMA patients: a neurobiologist s view. Neuromuscular Disorders 1995;5(5): Haddad 2003 Haddad H, Cifuentes-Diaz C, Miroglio A, Roblot N, Joshi V, Melki J. Riluzole attenuates spinal muscular atrophy disease progression in a mouse model. Muscle & Nerve 2003;28(4): Harada 2002 Harada Y, Sutomo R, Sadewa AH, Akutsu T, Takeshima Y, Wada H, et al.correlation between SMN2 copy number and clinical phenotype of spinal muscular atrophy: three SMN2 copies fail to rescue some patients from the disease severity. Journal of Neurology 2002;249(9): Higgins 2008 Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions The Cochrane Collaboration: Available from Updated September Iannaccone 1993 Iannaccone ST, Browne RH, Samaha FJ, Buncher CR. Prospective study of spinal muscular atrophy before age 6 years. DCN/SMA Group. Pediatric Neurology 1993;9(3): Iannaccone 1998 Iannaccone ST. Spinal muscular atrophy. Seminars in Neurology 1998;18(1): Iannaccone 2001 Iannaccone ST, Burghes AH. Spinal Muscular Atrophies. In: Rahman Pourmand, Yadollah Harati editor(s). Neuromuscular Disorders. Philadelphia: Lippincott Williams and Wilkins, 2001: Iannaccone 2003 Iannaccone ST, Hynan LS. American Spinal Muscular Atrophy Randomized Trials (AmSMART) Group. Reliability of 4 outcome measures in pediatric spinal muscular atrophy. Archives of Neurology 2003;60(8): Jablonka 2000 Jablonka S, Rossoll W, Schrank B, Sendtner M. The role of SMN in spinal muscular atrophy. Journal of Neurology 2000;247 Suppl 1:I Kariya 2008 Kariya S, Park GH, Maeno-Hikichi Y, Leykekhman O, Lutz C, Arkovitz MS, et al.reduced SMN protein impairs maturation of the neuromuscular junctions in mouse models of spinal muscular atrophy. Human Molecular Genetics 2008;17(16): [PUBMED: ] Kroksmark 2001 Kroksmark AK, Beckung E, Tulinius M. Muscle strength and motor function in children and adolescents with spinal muscular atrophy II and III. European Journal of Paediatric Neurology 2001;5(5): Lacomblez 1996 Lacomblez L, Bensimon G, Leigh PN, Guillet P, Meininger V. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II. Lancet 1996;347(9013): Lefebvre 1995 Lefebvre S, Burglen L, Reboullet S, Clermont O, Burlet P, Viollet L, et al.identification and characterization of a spinal muscular atrophy-determining gene. Cell 1995;80 (1): Lefebvre 1997 Lefebvre S, Burlet P, Liu Q, Bertrandy S, Clermont O, Munnich A, et al.correlation between severity and SMN protein level in spinal muscular atrophy. Nature Genetics 1997;16(3): Lefebvre 1998 Lefebvre S, Burglen L, Frezal J, Munnich A, Melki J. The role of the SMN gene in proximal spinal muscular atrophy. Human Molecular Genetics 1998;7(10): Lorson 1998 Lorson CL, Strasswimmer J, Yao JM, Baleja JD, Hahnen E, Wirth B, et al.smn oligomerization defect correlates with spinal muscular atrophy severity. Nature Genetics 1998;19 (1):63 6. Lorson 1999 Lorson CL, Hahnen E, Androphy EJ, Wirth B. A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proceedings of the National Academy of Sciences of the United States of America 1999;96(11): Lunn 2008 Lunn MR, Wang CH. Spinal muscular atrophy. Lancet 2008;371(9630): McWhorter 2003 McWhorter ML, Monani UR, Burghes AH, Beattie CE. Knockdown of the survival motor neuron (Smn) protein in zebrafish causes defects in motor axon outgrowth and pathfinding. The Journal of Cell Biology 2003;162(5): Melki 1990a Melki J, Abdelhak S, Sheth P, Bachelot MF, Burlet P, Marcadet A, et al.gene for chronic proximal spinal muscular atrophies maps to chromosome 5q. Nature 1990;344 (6268): Melki 1990b Melki J, Sheth P, Abdelhak S, Burlet P, Bachelot MF, Lathrop MG, et al.mapping of acute (type I) spinal muscular atrophy to chromosome 5q12-q14. The French Spinal Muscular Atrophy Investigators. Lancet 1990;336 (8710): Melki 1994 Melki J, Lefebvre S, Burglen L, Burlet P, Clermont O, Millasseau P, et al.de novo and inherited deletions of the 10

13 5q13 region in spinal muscular atrophies. Science 1994;264 (5164): Merlini 2002 Merlini L, Estournet-Mathiaud B, Iannaccone S, Melki J, Muntoni F, Rudnik-Schoneborn S, et al.90th ENMC international workshop: European Spinal Muscular Atrophy Randomised Trial (EuroSMART) 9-10 February 2001, Naarden, The Netherlands. Neuromuscular Disorders 2002;12(2): Merlini 2003 Merlini L, Solari A, Vita G, Bertini E, Minetti C, Mongini T, et al.role of gabapentin in spinal muscular atrophy: results of a multicenter, randomized Italian study. Journal of Child Neurology 2003;18(8): Miller 1996a Miller RG, Bouchard JP, Duquette P, Eisen A, Gelinas D, Harati Y, et al.clinical trials of riluzole in patients with ALS. ALS/Riluzole Study Group-II. Neurology 1996;47 Suppl 2 (4):S Miller 1996b Miller RG, Petajan JH, Bryan WW, Armon C, Barohn RJ, Goodpasture JC, et al.a placebo-controlled trial of recombinant human ciliary neurotrophic (rhcntf) factor in amyotrophic lateral sclerosis. rhcntf ALS Study Group. Annals of Neurology 1996;39(2): Miller 2001 Miller RG, Moore DH, Dronsky V, Bradley W, Barohn R, Bryan W, et al.a placebo-controlled trial of gabapentin in spinal muscular atrophy. Journal of the Neurological Sciences 2001;191(1-2): Miller 2007 Miller RG, Mitchell JD, Lyon M, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database of Systematic Reviews 2007, Issue 1. [DOI: / CD pub2] Munsat 1991 Munsat T. Workshop report: International SMA Collaboration. Neuromuscular Disorders 1991;1(2):81. Munsat 1992 Munsat TL, Davies KE. International SMA consortium meeting. (26-28 June 1992, Bonn, Germany). Neuromuscular Disorders 1992;2(5-6): Murray 2008 Murray LM, Comley LH, Thomson D, Parkinson N, Talbot K, Gillingwater TH. Selective vulnerability of motor neurons and dissociation of pre- and post-synaptic pathology at the neuromuscular junction in mouse models of spinal muscular atrophy. Human Molecular Genetics 2008;17(7): [PUBMED: ] NCT NCT Clinical trial of sodium phenylbutyrate in children with spinal muscular atrophy type I (NPTUNE 02). clinicaltrials.gov/show/nct (accessed 9 August 2011). NCT NCT Clinical trial of sodium phenylbutyrate in children with spinal muscular atrophy types II or III (NPTUNE01). clinicaltrials.gov/show/nct accessed 9 August NCT NCT Study to evaluate sodium phenylbutyrate in pre-symptomatic infants with spinal muscular atrophy (STOPSMA). clinicaltrials.gov/show/nct accessed 9 August NCT NCT Valproic acid and carnitine in infants with spinal muscular atrophy (SMA) type I. clinicaltrials.gov/ show/nct accessed 9 August Nicole 2002 Nicole S, Diaz CC, Frugier T, Melki J. Spinal muscular atrophy: recent advances and future prospects. Muscle & Nerve 2002;26(1):4 13. Oprea 2008 Oprea GE, Krober S, McWhorter ML, Rossoll W, Muller S, Krawczak M, et al.plastin 3 is a protective modifier of autosomal recessive spinal muscular atrophy. Science 2008; 320(5875): Oskoui 2007 Oskoui M, Levy G, Garland CJ, Gray JM, O Hagen J, De Vivo DC, Kaufmann P. The changing natural history of spinal muscular atrophy type I. Neurology 2007;69: Parker 2008 Parker GC, Li X, Anguelov RA, Toth G, Cristescu A, Acsadi G. Survival motor neuron protein regulates apoptosis in an in vitro model of spinal muscular atrophy. Neurotoxicity Research 2008;13(1): Parsons 1998 Parsons DW, McAndrew PE, Iannaccone ST, Mendell JR, Burghes AH, Prior TW. Intragenic telsmn mutations: frequency, distribution, evidence of a founder effect, and modification of the spinal muscular atrophy phenotype by censmn copy number. American Journal of Human Genetics 1998;63(6): Pellizzoni 1998 Pellizzoni L, Kataoka N, Charroux B, Dreyfuss G. A novel function for SMN, the spinal muscular atrophy disease gene product, in pre-mrna splicing. Cell 1998;95(5): Piepers 2008a Piepers S, De Jong S, Veldink JH, Van der Tweel I, van der Pol WL, Groeneveld GJ, et al.a randomised sequential trial of valproic acid in ALS. Abstracts of the American Academy of Neurology 60th Annual Meeting, April 12-19, 2008 Chicago USA. Marathon Multimedia, Piepers 2008b Piepers S, van den Berg LH, Brugman F, Scheffer H, Ruiterkamp-Versteeg M, van Engelen BG, et al.a natural history study of late onset spinal muscular atrophy types 3b and 4. Journal of Neurology. Epub ahead of publication [DOI: /s ] 11

14 Riviere 1998 Riviere M, Meininger V, Zeisser P, Munsat T. An analysis of extended survival in patients with amyotrophic lateral sclerosis treated with riluzole. Archives of Neurology 1998;55 (4): Russman 1992 Russman BS, Iannacone ST, Buncher CR, Samaha FJ, White M, Perkins B, et al.spinal muscular atrophy: new thoughts on the pathogenesis and classification schema. Journal of Child Neurology 1992;7(4): Russman 1996 Russman BS, Buncher CR, White M, Samaha FJ, Iannaccone ST. Function changes in spinal muscular atrophy II and III. The DCN/SMA Group. Neurology 1996;47(4): Ryan 2008 Ryan MM. The use of invasive ventilation is appropriate in children with genetically proven spinal muscular atrophy type 1: the motion against. Paediatric Respiratory Reviews 2008;9(1):51 4. Sumner 2007 Sumner CJ. Molecular mechanisms of spinal muscular atrophy. Journal of Child Neurology 2007;22(8): Swoboda 2005 Swoboda KJ, Prior TW, Scott CB, McNaught TP, Wride MC, Reyna SP, et al.natural history of denervation in SMA: relation to age, SMN2 copy number, and function. Annals of Neurology 2005;57(5): Takeuchi 1994 Takeuchi Y, Miyanomae Y, Komatsu H, Oomizono Y, Nishimura A, Okano S, et al.efficacy of thyrotropinreleasing hormone in the treatment of spinal muscular atrophy. Journal of Child Neurology 1994;9(3): Talbot 1999 Talbot K. Spinal muscular atrophy. Journal of Inherited Metabolic Diseases 1999;22(4): Thomas 1994 Thomas NH, Dubowitz V. The natural history of type I (severe) spinal muscular atrophy. Neuromuscular Disorders 1994;4(5-6): Thurmond 2008 Thurmond J, Butchbach ME, Palomo M, Pease B, Rao M, Bedell L, et al.synthesis and biological evaluation of novel 2,4-diaminoquinazoline derivatives as SMN2 promoter activators for the potential treatment of spinal muscular atrophy. Journal of Medicinal Chemistry 2008;51(3): Traynor 2003 Traynor BJ, Alexander M, Corr B, Frost E, Hardiman O. An outcome study of riluzole in amyotrophic lateral sclerosis - a population-based study in Ireland, Journal of Neurology 2003;250(4): Veldink 2001 Veldink JH, van den Berg LH, Cobben JM, Stulp RP, De Jong JM, Vogels OJ, et al.homozygous deletion of the survival motor neuron 2 gene is a prognostic factor in sporadic ALS. Neurology 2001;56(6): Wadman 2011 Wadman RI, Bosboom WMJ, van den Berg LH, Wokke JHJ, Iannaccone ST, Vrancken AFJE. Drug treatment for spinal muscular atrophy type II and III. Cochrane Database of Systematic Reviews 2011, Issue 12. Wang 2007 Wang CH, Finkel RS, Bertini ES, Schroth M, Simonds A, Wong B, et al.consensus statement for standard of care in spinal muscular atrophy. Journal of Child Neurology 2007; 22(8): Wirth 2000 Wirth B. An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Human Mutation 2000;15 (3): Wirth 2006a Wirth B, Brichta L, Hahnen E. Spinal muscular atrophy and therapeutic prospects. Progress in Molecular and Subcellular Biology 2006;44: Wirth 2006b Wirth B, Brichta L, Hahnen E. Spinal muscular atrophy: from gene to therapy. Seminars in Pediatric Neurology 2006; 13(2): Wirth 2006c Wirth B, Brichta L, Schrank B, Lochmuller H, Blick S, Baasner A, et al.mildly affected patients with spinal muscular atrophy are partially protected by an increased SMN2 copy number. Human Genetics 2006;119(4): Wokke 1996 Wokke J. Riluzole. Lancet 1996;348(9030): Wong 2007 Wong BL, Hynan LS, Iannaccone ST, AmSMART Group. A randomized, placebo-controlled trial of creatine in children with spinal muscular atrophy. Journal of Clinical Neuromuscular Disease 2007;8(3): Zerres 1995 Zerres K, Rudnik-Schoneborn S. Natural history in proximal spinal muscular atrophy. Clinical analysis of 445 patients and suggestions for a modification of existing classifications. Archives of Neurology 1995;52(5): Zerres 1997 Zerres K, Rudnik-Schoneborn S, Forrest E, Lusakowska A, Borkowska J, Hausmanowa-Petrusewicz I. A collaborative study on the natural history of childhood and juvenile onset proximal spinal muscular atrophy (type II and III SMA): 569 patients. Journal of the Neurological Sciences 1997;146 (1): Zerres 1999 Zerres K, Davies KE. 59th ENMC International Workshop: Spinal Muscular Atrophies: recent progress and revised diagnostic criteria April 1998, Soestduinen, The Netherlands. Neuromuscular Disorders 1999;9(4):

15 Zou 2007 Zou T, Ilangovan R, Yu F, Xu Z, Zhou J. SMN protects cells against mutant SOD1 toxicity by increasing chaperone activity. Biochemical and Biophysical Research Communication 2007;364(4): References to other published versions of this review Bosboom 2009 Bosboom WMJ, Vrancken AFJE, van den Berg LH, Wokke JHJ, Iannaccone ST. Drug treatment for spinal muscular atrophy type I. Cochrane Database of Systematic Reviews 2009, Issue 1. [DOI: / CD pub2] Wadman 2011b Wadman RI, Bosboom WMJ, van den Berg LH, Wokke JHJ, Iannaccone ST, Vrancken AFJE. Drug treatment for spinal muscular atrophy type I. Cochrane Database of Systematic Reviews 2011, Issue 12. [DOI: / CD pub3] Indicates the major publication for the study 13

16 C H A R A C T E R I S T I C S O F S T U D I E S Characteristics of included studies [ordered by study ID] Russman 2003 Methods Participants Interventions Outcomes Notes Randomised (2:1 ratio), placebo-controlled trial 10 children who fulfilled international classification criteria for SMA I and have a homozygous deletion of the SMN1 gene Riluzole orally, around 107 mg/m 2 /d or placebo. Duration of treatment 9 months, follow-up 12 months Number of children who died; age at death; adverse events Enrolment goal was 30 children with SMA type I, but only 10 children were included; until funding was withdrawn. Groups were not comparable at baseline, with earlier diagnosis and younger age in the placebo group. In riluzole group 3 children still alive without ability to sit at the age of 30, 48, and 64 months Risk of bias Bias Authors judgement Support for judgement Random sequence generation (selection bias) Low risk Randomly assigned Allocation concealment (selection bias) Unclear risk Randomly assigned (2:1), method not reported Blinding (performance bias and detection bias) All outcomes Incomplete outcome data (attrition bias) All outcomes Unclear risk Low risk Unknown Adequate Selective reporting (reporting bias) Low risk Adequate Other bias High risk Underpowered. Support from the pharmaceutical company was withdrawn so only 10 children could be included 14

17 Characteristics of excluded studies [ordered by study ID] Study Brichta 2006 Chang 2002 Franz 1995 Swoboda 2009 Reason for exclusion Not randomised. Study was on the effect of valproate on human SMN expression in blood Not randomised, not controlled. Only two participants Not randomised, not controlled Not randomised, not controlled; open label Characteristics of ongoing studies [ordered by study ID] NCT Trial name or title Methods Participants Interventions Outcomes A pilot therapeutic trial using hydroxyurea in children with SMA type I Randomised, placebo-controlled, double-blind trial Children with SMA type I up to 2 years old Hydroxyurea or placebo (dose route and duration of treatment not mentioned) Adverse events; length of survival (LOS) and age of ventilator dependence (AVD); Motor Unit Number Estimation (MUNE); biomarker assays: SMN protein and SMN mrna Starting date January 2004 Contact information Dr Ching H Wang, Stanford University School of Medicine, Stanford, California, United States, Notes This study is completed, but results have not yet been published 15

18 D A T A A N D A N A L Y S E S This review has no analyses. A D D I T I O N A L T A B L E S Table 1. Diagnostic criteria for SMA type I Age of onset before six months Symmetrical muscle weakness of limb and trunk Proximal muscles more affected than distal muscles and lower limbs more than upper limbs No abnormality of sensory function Serum creatine kinase (CK) activity not more than 10 times the upper limit of normal Denervation on electrophysiological examination, and no nerve conduction velocities below 70% of the lower limit of normal. There are no abnormal sensory nerve action potentials The muscle biopsy showing atrophic fibers of both types, hypertrophic fibers of one type (usually type I), and in chronic cases type grouping No involvement of the other neurological systems, such as the central nervous system, hearing or vision No involvement of non-neurological organs Genetic analysis to confirm the diagnosis, deletion or mutation of the SMN1 gene (5q ) Table 2. Outcome of included study Study Russman 2003 (Published data) Riluzole Placebo Number of participants randomised 7 3 Number (%) of participants evaluable for analysis 7 (100%) 3 (100%) Number of participants who died 4 3 Number (%) of participants who died 57% 100% Median age at death (months)

19 Table 2. Outcome of included study (Continued) Range of death (months) Adverse events 0 0 A P P E N D I C E S Appendix 1. MEDLINE OvidSP search strategy 1 randomized controlled trial.pt. 2 controlled clinical trial.pt. 3 randomized.ab. 4 placebo.ab. 5 drug therapy.fs. 6 randomly.ab. 7 trial.ab. 8 groups.ab. 9 or/ exp animals/ not humans.sh not exp Muscular Atrophy, Spinal/ 13 (Werdnig adj Hoffman$).mp. 14 (Kugelberg adj Welander).mp. 15 (spinal adj5 muscul$ adj5 atroph$).mp. 16 MUSCULAR DISORDERS, ATROPHIC/ 17 or/ and 17 Appendix 2. EMBASE OvidSP search strategy 1 crossover-procedure/ 2 double-blind procedure/ 3 randomized controlled trial/ 4 single-blind procedure/ 5 (random$ or factorial$ or crossover$ or cross over$ or cross-over$ or placebo$ or (doubl$ adj blind$) or (singl$ adj blind$) or assign$ or allocat$ or volunteer$).tw. 6 or/1-5 7 human/ 8 6 and 7 9 nonhuman/ or human/ 10 6 not or spinal muscular atrophy/ or hereditary spinal muscular atrophy/ 13 (Werdnig adj Hoffman$).mp. 14 (Kugelberg adj Welander).mp. 17

20 15 (spinal adj5 muscul$ adj5 atroph$).mp. 16 or/ and 16 Appendix 3. CENTRAL search strategy #1MeSH descriptor Muscular Atrophy, Spinal explode all trees #2(Werdnig NEAR Hoffman*) #3(Kugelberg NEAR Welander) #4MeSH descriptor Muscular Disorders, Atrophic explode all trees #5(#1 OR #2 OR #3 OR #4) Appendix 4. ISI Web of Knowledge search strategy Limits : Science Citation Index Expanded Conference Proceedings Citation Index -Science (CPCI-S) #1 TS=(random* trial) OR TS=(random* study) OR TS=(random* treatment) OR TS=(randomi* therap*) #2 TS=(placebo) OR TS=(blind*) OR TS=(control*) OR TS=(crossover) OR TS=(cross-over) #3 TS=(trial) OR TS=(study) OR TS=(treatment) OR TS=(treated) OR TS=(therap*) #4 TS=(random*) #5 #2 SAME #3 #6 #1 OR #5 #7 #4 AND #6 #8 TS=(spinal muscular atrophy) OR TS=(sma) OR TS=(hereditary spinal muscular atrophy) OR TS=(proximal spinal muscular atrophy) #9 TS=(Werdnig hofman*) OR TS=(werdnig) #10 TS=(Kugelberg) OR TS=(Welander) #11 TS=((cause* OR etiolog* OR origin) SAME (unknown OR without OR various OR variable OR different)) #12 #9 SAME #10 #13 #9 SAME #11 #14 #8 OR #12 OR #13 #15 TS=proximal OR TS=(juvenile OR intermediate OR infantile) #16 TS=(spinal muscular atrophy OR sma) #17 #15 SAME #16 #18 #14 OR #17 #19 #7 AND #18 Appendix 5. Clinical Trials Registry of the U.S. National Institute of Health search strategy 1 spinal muscular atrophy 2 treatment 18

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