Drug treatment for spinal muscular atrophy types II and III (Review)

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1 Drug treatment for spinal muscular atrophy types II and III (Review) 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 types II and III 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 types II and III. 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, which leads to progressive muscle weakness. Children with SMA type II do not develop the ability to walk without support and have a shortened life expectancy, whereas children with SMA type III develop the ability to walk and have a normal life expectancy. There are no known efficacious drug treatments that influence the disease course of SMA. 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 types II and III and to assess if such therapy can be given safely. Drug treatment for SMA type I is the topic of a separate updated Cochrane review. Search methods We searched the Cochrane Neuromuscular Disease Group Specialized Register (8 March 2011), Cochrane Central Register of Controlled Trials (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 March ). We also searched clinicaltrials.gov to identify as yet unpublished trials (8 March 2011). Selection criteria We sought all randomised or quasi-randomised trials that examined the efficacy of drug treatment for SMA types II and III. Participants had to fulfil the clinical criteria and have a deletion or mutation of the survival motor neuron 1 (SMN1) gene (5q ) that was confirmed by genetic analysis. The primary outcome measure was to be change in disability score within one year after the onset of treatment. Secondary outcome measures within one year after the onset of treatment were to be change in muscle strength, ability to stand or walk, change in quality of life, time from the start of treatment until death or full time ventilation and adverse events attributable to treatment during the trial period. 1

4 Data collection and analysis Two authors independently reviewed and extracted data from all potentially relevant trials. Pooled relative risks and pooled standardised mean differences were to be calculated to assess treatment efficacy. Risk of bias was systematically analysed. Main results Six randomised placebo-controlled trials on treatment for SMA types II and III were found and included in the review: the four in the original review and two trials added in this update. The treatments were creatine (55 participants), phenylbutyrate (107 participants), gabapentin (84 participants), thyrotropin releasing hormone (9 participants), hydroxyurea (57 participants), and combination therapy with valproate and acetyl-l-carnitine (61 participants). None of these studies were completely free of bias. All studies had adequate blinding, sequence generation and reports of primary outcomes. None of the included trials showed any statistically significant effects on the outcome measures in participants with SMA types II and III. One participant died due to suffocation in the hydroxyurea trial and one participant died in the creatine trial. No participants in any of the other four trials died or reached the state of full time ventilation. Serious side effects were infrequent. Authors conclusions There is no proven efficacious drug treatment for SMA types II and III. 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 types II and III Spinal muscular atrophy (SMA) is a neuromuscular disorder that results in progressive muscle weakness with onset in childhood and adolescence. There are three main types of SMA. Drug treatment for SMA type I is discussed in a separate Cochrane review. This review is of drug treatment for SMA types II and III. Both of these reviews were first published in 2009 and are now updated. The age of onset of SMA type II is between six and 18 months. Children with SMA type II will never be able to walk without support; they survive beyond two years and may live into adolescence or longer. The age of onset of SMA III, also known as Kugelberg-Welander disease, is after 18 months. Children with SMA type III develop the ability to walk at some time and their life expectancy is normal. From six randomised controlled trials, there is no evidence for a significant effect on the disease course when patients with SMA types II and III are treated with creatine (55 participants), phenylbutyrate (107 participants), gabapentin (84 participants), thyrotropin releasing hormone (9 participants), hydroxyurea (57 participants) or combination therapy with valproate and acetyl-l-carnitine (61 participants). The risk of bias of the included trials was systematically analysed and none of the studies were completely free of bias. Thus, there is still no known efficacious drug treatment for SMA types II and III. 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 in the spine and clinically manifests as progressive muscle weakness (Talbot 1999; Iannaccone 2001). Other parts of the peripheral nervous system such as the neuromuscular junction, and possibly the muscle, may be affected by disruption in maturation and development that is probably secondary to the deficiency of SMN protein (Braun 1995; Cifuentes-Diaz 2002; Kariya 2008; Murray 2008). The typical pattern of muscle weakness in SMA is weakness of the limbs, proximal more than distal, with the lower limbs involved earlier than the upper limbs (Thomas 1994; Kroksmark 2001). Intercostal muscles also become involved, 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 people with SMA is normal and at the end of the disease course there is often a striking discrep- 2

5 ancy between alertness and the ability to move (Thomas 1994; Iannaccone 1998). Electrophysiological examination shows denervation and reinnervation (Iannaccone 1998; Nicole 2002). There are three main types of SMA (Munsat 1991; Munsat 1992a; 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 intensive supportive care) die by the age of two years (Iannaccone 1993; Thomas 1994; Cobben 2008). SMA type 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 are never 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. Their 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 1992a). Although there are different subtypes, in fact SMA has a broad clinical spectrum. There is overlap between subtypes as there are, for instance, children with SMA without the ability to sit but with 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 also children with SMA with disease onset before six months who have 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 (types 0 to IV) is an autosomal recessive disease and these types 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, a full-length form (10%) that 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 messenger ribonucleic acid (mrna) splicing is probably dependent on the abundance of SMN protein (Lefebvre 1998; Pellizzoni 1998; Gendron 1999; Jablonka 2000). SMN 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 2001b; 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 3

6 or neurotrophic agents (Wirth 2006b; Lunn 2008; Thurmond 2008). Recently, gene conversion from the SMN2 gene to the SMN1 gene in human cells from SMA patients has been reported (DiMatteo 2008). Also, antisense application techniques are under investigation in preclinical trials (Hua 2007; Hua 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 SMAs type 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 an update of a review first published in Drug treatment for SMA type I 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 types II and III. 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 or adolescents with SMA types II and III. Primary outcomes 1. Change in disability score (for example Hammersmith Functional Motor Score, Motor Function Measure, Gross Motor Function Measure) as determined by the original study authors and, where possible, transformed to a Modified Rankin Scale (Merkies 2003). If necessary, authors were asked for the original data to enable this transformation. Secondary outcomes 1. Change in muscle strength (for example dynamometry, isometric strength testing, manual muscle testing (MMT)) as determined by the original authors and, where possible, transformed to a Medical Research Council (MRC) sum score (Merkies 2003). 2. Development of standing within one year after the onset of treatment. 3. Development of, or improvement in, walking within one year after the onset of treatment. 4. Change in the quality of life as determined by quality of life scales. 5. Change in forced vital capacity (FVC) as a percentage of FVC predicted for height. This was not stated in the original protocol but many trials used this as a measure of pulmonary function or the strength of respiratory muscles. 6. Time from beginning of treatment until death or full time ventilation (a requirement for 16 hours of ventilation out of 24 hours regardless of whether this was with tracheostomy, a tube or mask). 7. 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 using the outcome measures. The summary of outcome table will state the primary outcome measures, time from beginning of treatment until death or full time ventilation and adverse events. The adverse events will be specified by origin and severity. Types of participants Children or adolescents with SMA types II and III 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 Outcome measures were assessed within or up to one year after the onset of treatment and compared to baseline. Search methods for identification of studies Electronic searches We searched the Cochrane Neuromuscular Disease Group Specialized Register (8 March 2011), Cochrane Central Register of Controlled Trials (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). Searches were performed from 1991 onwards because at that time genetic analysis of the SMN1-gene became widely available and could be used to establish the diagnosis of SMA. We consulted the clinical trials registry of the U.S. 4

7 National Institute of Health (www.clinicaltrials.gov) (8 March 2011) to identify additional trials that had not yet been published. The following search terms, as MeSH terms and textwords (and their combinations and truncated synonyms), were adapted as appropriate to search each database: spinal muscular atrophy, atrophic muscular disorder, Kugelberg-Welander disease, Wohlfart-Kugelberg-Welander disease. For the search strategies see: Appendix 1 (MEDLINE), Appendix 2 (EMBASE), Appendix 3 (CENTRAL), Appendix 4 (ISI Web of Knowledge) and Appendix 5 (ClinicalTrials.gov). Searching other resources The reference lists of relevant cited studies, reviews, meta-analyses, textbooks, and conference proceedings were handsearched to identify additional studies. Readers are invited to suggest studies, particularly in other languages, which should be considered for inclusion. Data collection and analysis Selecting trials for inclusion For this updated review, two authors (RW and AV) independently checked titles and abstracts obtained from 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 methodological quality. Authors were not blinded to the trial author and source institution. Disagreement between the authors was resolved by reaching consensus. Assessment of methodological quality The methodological quality assessment took into account allocation concealment, security of randomisation, intention-to-treat analysis, patient 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 to be scored according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). Risk of bias was graded as low, high or unclear. Two authors (RW and AV) graded the methodological quality independently. In the case of disagreement, authors reassessed 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 reaching consensus or with third party adjudication if necessary. Statistical analysis We would have pooled only results of studies with the same class of drug treatment and performed analysis on SMA types II and III separately. 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. When Chi 2 analysis showed the data to be heterogeneous, we would have used a random-effects model with a maximum likelihood estimation. If no heterogeneity had been demonstrated, we would have used a fixed-effect model (Mantel-Haenszel risk ratio method). For continuous data, we would have calculated mean differences between the treatment and placebo groups for each study. Weighted mean differences (WMD) were to be calculated if data were sufficiently comparable between studies. If data were not sufficiently comparable between studies, the standard Review Manager (RevMan) generic inverse variance (GIV) analysis using treatment effect differences with their standard errors would have been used. Statistical uncertainty was expressed with 95% confidence intervals (CI). The trial investigators of two studies were contacted and provided raw data to facilitate these analyses (Miller 2001a; Wong 2007). 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, Kaplan-Meier survival analysis would have been performed. Statistical considerations would have involved a trade-off between bias and precision. Risk of bias was to be assessed as unclear when too few details were available to make a judgement of high or low risk, when the risk of bias was genuinely unknown despite sufficient information about the conduct of the study, or when an entry was not relevant to a study. All studies were to 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 reviewed the results from open and uncontrolled studies. In addition, adverse events found in this review are discussed in relation to the side effects of drugs reported in the non-randomised literature. R E S U L T S 5

8 Description of studies See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification; 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), CENTRAL 52 (11 new) and ISI Web of Knowledge 418 (23 new). We identified and assessed 23 studies (7 new) for possible inclusion in the review. Seventeen studies were excluded (see Table Characteristics of excluded studies) because they were not randomised or were uncontrolled, or clinical outcome measures were not assessed (Folkers 1995; Chang 2002; Kinali 2002; Merlini 2003; Mercuri 2004; Brahe 2005; Brichta 2006; Weihl 2006; Tsai 2007; Liang 2008; Pane 2008; Kato 2009; Nascimento 2009; Swoboda 2009; Piepers 2010; Abbara 2011). We could not obtain the results of the EUROsmart trial (Merlini 2007), a placebo-controlled trial of acetyl-l-carnitine in SMA. See Characteristics of studies awaiting classification. Six trials remained that fulfilled the selection criteria (see Included studies). There were no studies with the same class of drug treatment. Just one study only included patients with SMA type II (Mercuri 2007) whereas the other five studies did not make a distinction between the subtypes (Tzeng 2000; Miller 2001a; Wong 2007; Chen 2010; Swoboda 2010). Results of the primary and secondary outcome measures of the included studies that are relevant to this review are reported in the Results section. Otherwise, only the primary outcomes as defined by the study investigators of the included studies are detailed below. endpoints were change in electrodiagnostic measures and the occurrence of side effects related to the treatment. Oral gabapentin versus placebo Miller 2001 This double-blind randomised placebo-controlled trial compared oral gabapentin 1200 mg three times a day with placebo in a total of 84 patients aged at least 21 years. Duration of treatment was 12 months with follow-up at quarterly intervals while on the treatment. Muscle strength was measured bilaterally by maximum voluntary isometric contraction (MVIC) of elbow flexion and hand grip. Linear regression analysis was used to determine the change in muscle strength, forced vital capacity (FVC), Spinal Muscular Atrophy Functional Rating Scale (SMAFRS) and a combined measure of the functional capacity of the lower limbs and quality of life (mini Sickness Impact Profile: mini SIP) over time. Treatment efficacy was determined by comparing the average percentage change for the treatment and placebo groups in the intentionto-treat population (defined as participants with at least two study visits: 37 participants in the treatment group and 39 participants in the placebo group) using the Mann-Whitney test. The primary endpoint was the average percentage change in muscle strength from baseline. Secondary endpoints were the average percentage change of FVC, SMAFRS and mini SIP from baseline, and the occurrence of adverse events. These primary and secondary endpoints are discussed in the Results section. Included studies Oral phenylbutyrate versus placebo Intravenous thyrotropin releasing hormone versus placebo Tzeng 2000 This double-blind randomised placebo-controlled trial compared intravenous (i.v.) thyrotropin releasing hormone (TRH) 0.1 mg/ kg once a day with placebo. Six patients were treated and three patients received placebo. Duration of treatment was 29 days over a 34-day period with follow-up and conclusion of the study at five weeks. Muscle strength was evaluated by dynamometry of the deltoids, biceps, triceps, wrist extensors, hand grip, hip flexors, quadriceps, and hamstrings. Comparisons of total mean muscle strength and electrodiagnostic measures at baseline and at the end of the five-week study period were made using paired t-tests. The primary endpoint was the change in total mean muscle strength from baseline, discussed in the Results section. Secondary Mercuri 2007 This phase II double-blind randomised placebo-controlled trial compared oral phenylbutyrate 500 mg/kg/d, divided into five doses and using an intermittent schedule (seven days on treatment, seven days off treatment), with placebo in a total of 107 patients with SMA type II. Duration of treatment was 13 weeks with follow-up at the end of the study period (also at 13 weeks). Motor function was assessed in all patients. In addition muscle strength and FVC were assessed in children older than five years. Muscle strength was measured by handheld dynamometry of elbow flexion, hand grip, three point pinch, knee flexion and knee extension; the best scores were added to obtain an arm megascore and a leg megascore. Treatment efficacy was evaluated by intention-to-treat analysis in 90 patients (45 in the treatment group and 45 in the placebo group) with continuous endpoints at five and 13 weeks followup using analysis of covariance (ANCOVA) which included the baseline outcome values as covariates, treatment group and age 6

9 as between-patient factors, time as a within-patient factor, and possible interaction between treatment group, time and age. The primary endpoint was the change in Hammersmith Functional Motor Scale from baseline. Secondary endpoints were the change in muscle strength and FVC from baseline and the occurrence of side effects or adverse events. These primary and secondary endpoints are discussed in the Results section. Oral creatine versus placebo Wong 2007 This double-blind randomised placebo-controlled trial compared oral creatine with placebo in 55 patients divided into two age groups. Of the 22 participants aged two to five years, 10 received 2 g of creatine once a day and 12 received placebo. Of the 33 participants aged 5 to 18 years, 17 received 5 g of creatine once a day and 16 received placebo. Duration of treatment was six months with follow-up at nine months. Muscle strength for knee extension, knee flexion, and elbow flexion were measured bilaterally with the Richmond Quantitative Measurement System. Hand grip strength was measured bilaterally with handheld dynamometry. The best scores were added to obtain a total, upper body, and lower body quantitative muscle testing (QMT) score. Treatment efficacy for each age group was evaluated by intentionto-treat analysis of continuous endpoints using ANCOVA, which included the qualifying screening measure as the baseline covariate, treatment group as between-subject effect, time as within-subject effect, and a subject by time interaction. The primary endpoint was the change in Gross Motor Function Measure (GMFM) from baseline. Secondary endpoints were the changes in muscle strength and pulmonary function tests (for example FVC) from baseline in children five to 18 years of age, and change in quality of life (assessed by a neuromuscular module of the parent questionnaire for the paediatric quality of life PedsQL T M ) from baseline. These primary and secondary endpoints are discussed in the Results section. Oral valproic acid (valproate) in combination with acetyl-lcarnitine versus placebo Swoboda 2010 This double-blind placebo-controlled trial compared combination therapy with oral valproate and acetyl-l-carnitine to placebo in 61 non-ambulatory children aged between two and eight years. Thirty-one children received treatment with 125 mg valproate given in divided doses two to three times a day and sufficient to maintain overnight trough levels of 100 mg/dl and acetyl-l-carnitine doses at 50 mg/kg/day divided into two daily doses. Thirty children received a double placebo. The duration of treatment was 12 months in the active treatment arm and six months in the placebo. After six months the placebo group switched over to active treatment per protocol. In all participants the Modified Hammersmith Functional Motor Scale (MHFMS) and Gross Motor Function Measure (GMFM) were used to measure functional motor ability at baseline, three, six and 12 months after the start of treatment. The degree of innervation by the ulnar nerve was estimated using maximum ulnar compound muscle action potential (CMAP) amplitude. Myometry measurements were performed in children aged five years and older (24 children) with no significant contractures: three times for right and left elbow flexion and for right and left knee extension. Also in the children aged five years and older, pulmonary function testing was performed, which included FVC, forced expiratory volume and maximum inspiratory and expiratory pressures. Quality of life was assessed using the PedsQL, filled in by parents at each visit. Children aged five years or older completed the age-appropriate PedsQL. Bone mineral density and bone mineral content were measured with dual-energy X-ray absorptiometry (DEXA). All analyses were performed on an intention-to-treat population of 61 persons that was defined as all participants randomised to receive study medication. The analysis of variance (ANOVA) test was used to compare treatment groups for change in MHFMS from the baseline data. Non-normally distributed data were tested with the Wilcoxon rank sum test. The primary endpoints were laboratory safety data, adverse event data and change in MHFMS from baseline after six months. Secondary endpoints included measurement from baseline at six and 12 months in MHFMS, estimates of CMAPs, DEXA, body composition and bone density, quantitative SMN mrna and quality of life using PedsQL T M. These primary and secondary endpoints are discussed in the Results section. Oral hydroxyurea versus placebo Chen 2010 This phase II/III double-blind randomised placebo-controlled trial compared oral hydroxyurea with placebo in 57 participants with SMA types II and III aged above five years. Participants received an escalated daily dose over four weeks to a final daily dose of 20 mg/kg/day hydroxyurea or placebo. For the first four weeks participants received 10 mg/kg/day and for the second four weeks the dose was escalated to 15 mg/kg/day. After eight weeks participants received the final dose. Duration of treatment was 18 months. Follow-up of post-treatment effects was at six months. The safety and tolerability of hydroxyurea were measured through serum level measurement. Muscle strength and motor function were measured with the Manual Muscle Testing (MMT) and the Gross Motor Function Measure (GMFM). The GMFM and MMT were performed in all 57 participants. The MHFMS was performed in 28 participants with SMA type II and 10 participants with SMA type III who were already non-ambulatory at the begin- 7

10 ning of the trial. Lung function was evaluated by FVC measurements. In all patients quantitative full-length SMN mrna was measured. Adverse events and serious adverse events were monitored at each assessment by a complete blood count, chemistry profiles of liver and renal function, and completion of a questionnaire. Treatment efficacy was evaluated by intention-to-treat analysis with a last observation carried forward approach. Changes in GMFM, MHFMS, MMT, FVC and serum flsmn mrna were analysed by analysis of covariance (ANCOVA). Measures at time points of the treatment period and the post-treatment period for primary and secondary endpoints were compared by mixed models with adjusted covariates. A 2-tailed t-test was used to compare the incidence of adverse events and serious adverse events during the treatment phase. The primary endpoints were the GMFM, MMT and serum full-length SMN mrna level. Secondary endpoints were the MHFMS and FVC. These primary and secondary endpoints are discussed in the Results section. Risk of bias in included studies The methodological quality scores for the six included trials are shown in the Characteristics of included studies tables and summarised in Figure 1. The randomisation method was not clear in two trials (Miller 2001a; Chen 2010); in the other four trials it was adequate. Allocation concealment was not clear in one trial (Chen 2010). Blinding of parents, participants and observers, and diagnostic criteria for inclusion, were adequate in all trials. In two trials there were baseline differences (Wong 2007; Swoboda 2010). In one trial (Wong 2007) there were baseline differences for children aged five to 18 years as the creatine treatment group was slightly weaker than the placebo group at baseline. In one trial (Swoboda 2010) there were baseline differences in gender as the valproate in combination with acetyl-l-carnitine treatment group consisted of 36.6% females compared to 56% females in the placebo group, and there were differences in body mass index. Follow-up was below 80% in two trials (Miller 2001a; Wong 2007). Primary outcome measures were adequately stated in all trials. 8

11 Figure 1. Risk of bias summary: review authors judgements about each risk of bias item for each included study. 9

12 Effects of interventions We could not perform meta-analysis because there were no trials with the same class of drug treatment. We re-analysed the data from three trials according to our predefined primary and secondary outcome measures (Tzeng 2000; Miller 2001a; Wong 2007). To enable this analysis, the raw study data were obtained from the principal investigators of two studies (Miller 2001a; Wong 2007). The results of this re-analysis are shown separately for each included trial in Table 2, Table 3, Table 4, Table 5, Table 6 and Table 7. Primary outcome measure Change in disability score Change in disability was an outcome in five trials. It was not possible to transform the different disability scales to the Modified Rankin Scale. The scales used were the GMFM (Wong 2007; Chen 2010), Hammersmith Functional Motor Score (HFMS) ( Mercuri 2007; Swoboda 2010), and the SMA-FRS (Miller 2001a). There were no significant differences for change in disability scores between the treatment and placebo groups in any of these five trials. Secondary outcome measures (1) Change in muscle strength All six included trials measured muscle strength via quantitative myometry, but no significant differences were found for change in hand, arm, feet, leg or total muscle strength between the treatment and placebo groups. In one trial (Miller 2001a) some patients were not able to perform all of the muscle strength tests and these patients were therefore not included in the analyses. Moreover, the raw data from this trial showed several extreme values of muscle strength in one particular participating centre. We therefore re-analysed the data with and without these outliers but this did not result in a different statistical outcome. For a limited number of patients in this trial, data were available at 12 months follow-up. Re-analysis of these limited data (shown in Table 3, Outcome of study Miller 2001a ) also showed no difference for change in muscle strength between the treatment and placebo groups. In another trial (Tzeng 2000), a significant improvement in muscle strength was reported in one patient treated with thyrotropin releasing hormone. No comparison was made by the study investigators between the treatment and placebo groups because the study size was considered too small, but our re-analysis of their published data did not show a significant difference for change in muscle strength. (2) Development of standing There were no data on standing in any of the six included trials. (3) Development of walking Data on the development of walking were available in only one trial (Miller 2001a). None of the patients who were unable to walk before treatment achieved this ability after treatment, and none of the patients who could walk lost this ability in either the treatment or placebo group. No significant difference between the treatment and placebo group was found for the development of walking, with a relative risk at nine months follow-up of 1.1 (95% CI 0.51 to 2.4) and a relative risk at 12 months follow-up of 0.87 (95% CI 0.38 to 2.0). (4) Change in quality of life Quality of life was measured in three trials (Miller 2001a; Wong 2007; Swoboda 2010). No significant differences were found for a change in quality of life between the treatment and placebo groups in either trial. In one trial (Swoboda 2010) there was no statistically significant association between quality of life and change in MHFMS, but there was a non-significant trend towards deterioration of quality of life as MHFMS declined. (5) Change in pulmonary function The change in forced vital capacity (FVC), in percentage of normal values, was measured in patients older than five years in four trials (Mercuri 2007; Wong 2007; Chen 2010; Swoboda 2010) and in all patients in another trial (Miller 2001). No significant differences were found between the treatment and placebo groups in any of these four trials. One trial (Swoboda 2010) had insufficient power (24 patients aged five years and older) to observe a statistically significant association. (6) Time from beginning of treatment until death or full time ventilation Except for the trial with creatine, in which one participant in the placebo group died (Wong 2007), and the trial with hydroxyurea in which one participant in the treatment group died (Chen 2010), no other deaths were reported and none of the participants reached the state of more than 16 hours ventilation a day. 10

13 (7) Adverse effects, separated into severe and others Five trials reported data on adverse effects; only two trials specified the sort of adverse effects. In one trial six participants treated with TRH had 12 adverse events compared to no adverse events in the placebo group (Tzeng 2000). In another trial two of 54 participants treated with phenylbutyrate, compared with one of 53 participants who received placebo, had adverse effects and among these in each group only one had a severe adverse event (Mercuri 2007). In the third trial 13 of 27 participants treated with creatine and 16 of 28 participants who received placebo had an adverse effect; the authors were not able to provide data on severe adverse effects on request (Wong 2007). In one trial with hydroxyurea all patients had at least one adverse event and 33% of 61 participants had a severe adverse event. There were 224 adverse events in 37 participants treated with hydroxyurea and 129 adverse events in the placebo group of 20 participants. Severe adverse events occurred 19 and 10 times in the hydroxyurea group and placebo group respectively (Chen 2010). In one trial 77% of the 30 patients receiving treatment with valproate and acetyl-l-carnitine had one or more adverse event compared to 58% of the 31 participants in the placebo group. Severe adverse events occurred in 20% of the participants treated with valproate and acetyl-l-carnitine and in 6% of the placebo group. Although (severe) adverse events occurred more often in the active treatment group this difference in occurrence was not significant (Swoboda 2010). The authors of one trial could not provide data on adverse effects (Miller 2001a). D I S C U S S I O N Six randomised controlled trials (RCTs) have been performed to evaluate the efficacy of drug treatment in patients with SMA types II and III (Tzeng 2000; Miller 2001a; Mercuri 2007; Wong 2007; Chen 2010; Swoboda 2010); one of these trials included only patients with SMA type II (Mercuri 2007). One trial included only non-ambulatory patients with SMA types II and III (Swoboda 2010). The treatments investigated were intravenous thyrotropin releasing hormone (TRH), oral gabapentin, oral phenylbutyrate, oral creatine, oral hydroxyurea, and oral combination therapy with valproate and oral acetyl-l-carnitine. Although open and uncontrolled trials with these drugs had seemed promising, the six RCTs did not show any efficacy on any of the outcome measures in patients with SMA types II and III (Tzeng 2000; Miller 2001a; Mercuri 2007; Wong 2007; Chen 2010; Swoboda 2010). We discuss the results of treatment with each of these drugs from trials in SMA and in other neuromuscular diseases, especially other motor neuron diseases. The precise mechanisms of action of TRH, a tripeptide produced by the hypothalamus, are unknown. It has a neurotrophic effect on spinal motor neurons of SMA patients (Takeuchi 1994). An effect of TRH in SMA was considered since an uncontrolled study found improvements in motor function and electromyographic findings in patients with SMA types II and III after thyrotropin releasing hormone therapy (Takeuchi 1994). The small RCT with TRH in patients with SMA types II and III that was included in this review did not show objective differences between the TRH treatment group and the placebo group, although there were a few anecdotal improvements after treatment with TRH (Tzeng 2000). However, the trial was too small to draw any conclusions about the efficacy of treatment with TRH. In amyotrophic lateral sclerosis (ALS) some controlled trials with intravenous or subcutaneous administration of TRH or TRH analogues did show significant improvements on some outcome measures, but the effect was temporary and disease progression was not halted with any of the TRH analogues (Caroscio 1986; Brooke 1989; Guiloff 1989). Other studies did not show any positive effect of intravenous, subcutaneous, intramuscular or intrathecal treatment with TRH or TRH analogues compared with placebo (Brooke 1986; Mitsumoto 1986; Bradley 1990; Munsat 1992b). Gabapentin It is thought that gabapentin has a neuroprotective role by diminishing the excitotoxicity potential of glutamate (Greensmith 1995; Taylor 1998; Merlini 2003). In a large randomised unblinded and uncontrolled trial with gabapentin in 120 patients with SMA types II and III, a trend for improvement in the strength of the arms, a significant improvement in muscle strength of the legs and in time walked in favour of gabapentin treatment were observed at 12 months, with no effect on forced vital capacity (FVC) or functional tests (Merlini 2003). Because this trial was neither blinded nor placebo-controlled, one cannot draw conclusions regarding the efficacy of gabapentin. In fact, the RCT included in this review did not demonstrate any efficacy of gabapentin in adult patients aged 21 years or older with SMA types II and III (Miller 2001a). An unblinded and uncontrolled randomised trial on treatment with gabapentin in ALS showed a slower decline in muscle strength in all gabapentin treated groups and a longer survival in the two groups treated with higher cumulative doses of gabapentin (Mazzini 1998). A phase II randomised controlled trial in ALS observed a trend towards a slower decline in muscle strength (Miller 1996b). However, in the subsequent large phase III randomisedcontrolled trial, there was no evidence of a beneficial effect of gabapentin on disease progression or symptoms in patients with ALS (Miller 2001b). Thyrotropin releasing hormone (TRH) Phenylbutyrate 11

14 Phenylbutyrate is one of the histone deacetylase inhibitors and a few studies have suggested a therapeutic role for these agents in SMA as they appeared to increase the expression of SMN2 (Kernochan 2005; Wirth 2006a; Darras 2007). Histone deacetylase inhibitors also display a neuroprotective capacity against oxidative stress in vitro (Rouaux 2007). In fibroblast cultures and leucocytes of patients with SMA and treated with phenylbutyrate, the drug was able to increase the SMN transcript expression (Andreassi 2004; Brahe 2005). Also, based on the results from a pilot study with phenylbutyrate a positive effect on the disease course of SMA was expected (Mercuri 2004). In this uncontrolled trial, a functional improvement was found in 10 patients with SMA type II after nine weeks of treatment with oral phenylbutyrate (Mercuri 2004). However, the large RCT in SMA type II patients included in this review did not show any efficacy after three months of treatment (Mercuri 2007). A multicenter phase I/II trial evaluating multiple dosage levels of sodium phenylbutyrate to determine the maximum tolerated dose or the highest dose that can be safely given to children with SMA types II or III was terminated due to poor compliance to the study drug administration (NCT ). A phase I/II study on sodium phenylbutyrate in presymptomatic infants genetically confirmed to have SMA, probable SMA type II (and type I), is ongoing (for details see NCT ). Creatine Creatine may confer therapeutical benefit by increasing muscle mass and strength through its role as an energy shuttle between mitochondria and working musculature, and it could also exert neuroprotective effects (Bessman 1981; Tarnopolsky 1999; Ellis 2004). In the RCT in patients with SMA types II and III that was included in this review, there was no evidence for a therapeutic effect of oral creatine (Wong 2007). Also, in ALS two large randomised placebo-controlled trials on treatment with creatine did not demonstrate improvements in overall survival, functional measurements or muscle strength (Groeneveld 2003; Shefner 2004). Two small randomised placebo-controlled trials and a Cochrane review on oral creatine for hereditary muscle diseases found muscle strength improvement in muscular dystrophies but no effect in metabolic myopathies (Walter 2000; Schneider-Gold 2003; Kley 2011). Two other Cochrane reviews on treatment in facioscapulohumeral dystrophy (Rose 2004) and Charcot-Marie-Tooth disease (Young 2008) did not show any effect of creatine. Valproate One of the drugs that showed positive results in in vitro and open label studies is valproate (Brichta 2003; Sumner 2003; Brichta 2006). This is a histone deacetylase inhibitor that increases SMN protein in vitro by increasing transcription of SMN2 genes (Kernochan 2005; Weihl 2006) and has an antiglutamatergic effect (Kim 2007). Glutamate is released after presynaptic depolarisation and if the amino acid is not efficiently cleared this leads to increased levels of free radicals and eventually degeneration of motor neurons (Bryson 1996). A retrospective uncontrolled open label study reported improvement in seven adult patients with SMA types III and IV during treatment with valproate (Weihl 2006). In another retrospective uncontrolled open label study global muscle strength improved in two children and one adolescent with SMA types II and III, but no effect was observed in the other adolescent and two adults (Tsai 2007). A large randomised trial is needed to establish the possible efficacy of valproate in patients with SMA. A phase II trial in patients with SMA types II and III aged above 18 years is ongoing (NCT ). A randomised placebo-controlled trial of valproate in 163 patients with ALS found no evidence for a beneficial effect (Piepers 2008a). In the recent phase II trial in non-ambulatory patients with SMA types II and III that was included in this review, combination therapy with valproate and acetyl-l-carnitine, showed no significant improvement of motor function and muscle strength (Swoboda 2010). An open label trial with valproic acid and carnitine in patients with SMA types II and III is ongoing (NCT ). Hydroxyurea Hydroxyurea is another histone deacetylase inhibitor. In vitro, hydroxyurea did increase SMN2 gene expression and production of SMN protein in cultured lymphocytes of SMA patients (Grzeschik 2005; Liang 2008). In an uncontrolled open label trial in two patients with SMA type I, five patients with SMA type II and two patients with SMA type III, hydroxyurea showed an improvement in muscle strength without side effects (Chang 2002). A larger randomised uncontrolled trial from the same investigators included 33 patients with SMA types II and III who were treated for eight weeks with three different doses of hydroxyurea. SMN gene expression was enhanced and there was a trend towards improvement in some clinical outcome measures (Liang 2008). There were no trials on treatment with hydroxyurea in other neuromuscular diseases. Thus hydroxyurea seems to be safe in patients with SMA types II and III but a possible efficacy was not established in the large RCT in 57 patients that was included in this review (Chen 2010). One randomised, double-blind, placebo-controlled trial in children with SMA types II and III is ongoing (NCT ). Altogether, from the six RCTs included in this review, it can be concluded that there is no evidence for efficacy of one month treatment with intravenous thyrotropin releasing hormone, 12 months treatment with oral gabapentin, three months treatment with oral phenylbutyrate, six months combination treatment with valproate and acetyl-l-carnitine, 18 months treatment with oral hydroxyurea or six months treatment with oral creatine in patients with SMA types II and III. From the RCTs with these drugs in other neuromuscular disorders, especially ALS, there is also no 12

15 evidence for a therapeutic effect except for oral creatine in muscular dystrophies. Other drugs that seem promising in open and uncontrolled trials in patients with SMA are described below. However a placebo effect is often underestimated and conclusions about efficacy should only be drawn from RCTs. Carnitine L-carnitine, an essential cofactor for the beta-oxidation of longchain fatty acids, inhibits mitochondrial injury and apoptosis both in vitro and in vivo. A mitochondrial abnormality has been reported in patients with ALS and animal models of ALS (Kira 2006). Treatment with L-carnitine increased mitochondrial enzyme activities, delayed the onset of motor behaviour impairment and increased the life span in animal models of ALS (Bertamini 2002; Kira 2006). A decrease of carnitine was found in muscles of patients with SMA type I and L-carnitine treatment restored the level of free carnitine to normal in an animal model (Bresolin 1984). Also, valproate-mediated carnitine insufficiency can be attenuated by L-carnitine supplementation (Gibal 1997). Acetyl-Lcarnitine, the non-acetylated derivative of L-carnitine, has neuroprotective and neurotrophic activity in motoneuron cultures (Bigini 2002). An RCT of treatment with acetyl-l-carnitine in 110 patients with SMA types II and III has been completed but results are not yet available (Merlini 2007). Salbutamol Some studies have documented an effect of oral beta 2 -adrenoceptor agonists on human skeletal muscle (Martineau 1992; Caruso 1995; Kindermann 2007). In SMA fibroblasts, salbutamol has been shown to increase the SMN2 full-length mrna and the SMN protein (Angelozzi 2008). In an open label pilot trial that included 13 patients with SMA types II and III, there was a significant increase in muscle strength measured by myometry and FVC after six months of salbutamol treatment. The therapy was generally well tolerated but in several patients an increase in contractures was seen, which could reflect a stronger effect of salbutamol on agonist muscles (Kinali 2002). In a second open trial involving 23 patients with SMA type II, the functional scores were significantly higher after six and 12 months of treatment with salbutamol and there were no major side effects (Pane 2008). A pilot trial with salbutamol in children with central core and multi-minicore diseases also demonstrated an increase in functional abilities and muscle strength (Messina 2004). In a randomised placebo-controlled trial involving 90 patients with facioscapulohumeral muscular dystrophy, salbutamol did show some effect on secondary outcome measures but no overall effect on muscle strength or function (Kissel 2001; Rose 2004). In addition, salbutamol failed to have any effect on pain and fatigue in a randomised placebocontrolled trial in 56 patients with facioscapulohumeral muscular dystrophy (van der Kooi 2007). In a pilot trial in patients with ALS, clenbuterol, another beta 2 -adrenoceptor agonist, could not demonstrate therapeutic effects (Soraru 2006). Riluzole Riluzole is thought to have a neuroprotective effect on motor neurons by blocking the presynaptic release of glutamate. It has been proven to be modestly effective in slowing disease progression in amyotrophic lateral sclerosis (ALS) (Bensimon 1994; Lacomblez 1996a; Miller 1996a; Riviere 1998; Traynor 2003; Miller 2007) with only minimal adverse effects (Wokke 1996). Surprisingly few studies have investigated the effect of riluzole in SMA, but riluzole has been shown to attenuate disease progression in an SMA mouse model (Haddad 2003). There has been one randomised controlled study with riluzole in SMA type I (Russman 2003) and this is analysed and discussed in a separate Cochrane Review (Wadman 2011). Briefly, this trial could not demonstrate an effect of riluzole in SMA type I because the power of this study was very low and the treatment and placebo groups were not comparable at baseline. However, three children with SMA type I who were treated with riluzole were still alive at the age of 30, 48 and 64 months, respectively, whereas in the placebo group all patients died (Russman 2003). An RCT with riluzole in SMA types II and III is ongoing (NCT ). From studies on coenzyme Q10, lithium carbonate and guanidine hydrochloride, it was not clear on clinical grounds whether the patient population consisted only of patients with SMA type II or III (Angelini 1980; Il ina 1980; Folkers 1995) because SMN gene analysis was not possible prior to For example, four patients in one of these studies had pseudohypertrophy of the calves, suggesting a neuromuscular disease other than SMA (Angelini 1980). Therefore, we have not discussed the therapeutic effects of these drugs. Other neurotrophic factors Besides thyrotropin releasing hormone (TRH), other neurotrophic factors are considered as potential therapy for motor neuron diseases (Apfel 2001). In a phase I trial of treatment with recombinant human ciliary neurotrophic factor (CNTF) in patients with SMA type I no serious side effects were noted (Franz 1995). In a mouse model of SMA, cardiotrophin-1 seemed effective in slowing down disease progression (Lesbordes 2003); glial cell line derived neurotrophic factor, brain-derived neurotrophic factor (BDNF), CNTF, insulin-like growth factor I (rhigf-i) and neurotrophin-3 (via adenovirus mediated gene transfer) were also promising in studies on ALS animal models (Zurn 1996; Haase 1997; Bilak 2001; Bordet 2001; Cabanes 2007). However, two randomised placebo-controlled trials on CNTF in 570 and

16 patients with ALS and a meta-analysis were negative (ACTS 1996; Miller 1996c; Bongioanni 2004). In a randomised placebo-controlled trial of BDNF in 1135 patients with ALS, there was a trend toward increased survival (BDNF Study Group 1999). A placebocontrolled pilot trial on intrathecal BDNF in 10 patients with ALS did not show an effect on autonomic function tests (Beck 2005). Treatment with xaliproden, a rhigf-i analogue, did show a favorable trend on disease progression of ALS in two randomised placebo-controlled trials (Meininger 2004). A randomised controlled pilot study of growth hormone treatment in patients with SMA types II and III is ongoing (NCT ). The experimental drug olesoxime (cholest-4-en-3-one, oxime) is thought to modulate the mitochondrial permeability transition pore (mptp) opening, a critical step in cell apoptosis which is the mechanism by which motor neuron death is thought to occur in SMA and ALS (Bordet 2008). Olesoxime showed neuroprotective and neuroregenerative effects in four animal models of motor nerve degeneration, as well as antinociceptive and neuroprotective effects in experimental models of painful peripheral neuropathies. A phase II clinical trial in 185 patients with painful peripheral diabetic neuropathy has been completed providing evidence that the compound is safe in diabetic patients exposed to this agent for six weeks (NCT ). A pivotal 18-month ALS European multicenter study was initiated in April 2009 and is still ongoing (NCT ). A randomised placebo-controlled trial of olesoxime in children and adolescents with SMA types II and III was initiated in November 2010 and is ongoing (NCT ). Other glutamate inhibitors and antioxidants Lamotrigine, a glutamate inhibitor like riluzole, did not show a clinical effect on ALS in a randomised placebo-controlled trial (Ryberg 2003). A randomised placebo-controlled trial in patients with ALS could not demonstrate a beneficial effect of treatment with a high dose of the antioxidant vitamin E (Graf 2005), although in another randomised placebo-controlled trial patients with ALS who were treated with vitamin E remained in a milder disease state longer (Desnuelle 2001). Other agents increasing the expression of SMN protein levels A new direction for the development of drugs for patients with SMA are agents that are capable of increasing the expression of SMN protein levels. It has been shown that the cellular ph microenvironment can modulate pre-mrna alternative splicing in vivo. In SMA cells 5-(N-ethyl-N-isopropyl)-amiloride, a Na + /H + exchange inhibitor, significantly increased SMN2 exon 7 inclusion and SMN protein production (Yuo 2008). PTK-SMA1, a tetracycline-like compound, stimulates exon 7 splicing and increases SMN protein levels in vitro and in vivo (Hastings 2009). Also, a 2,4-diaminoquinazoline derivative induced SMN protein in cells of a patient with SMA type I (Thurmond 2008), ameliorated phenotype and increased survival in a SMA mouse model (Butchbach 2010). Experimental histone deacetylase (HDAC) inhibitors, like (E)-resveratrol, seem to increase the level of full-length SMN2 mrna and protein in in vitro studies (Dayangac-Erden 2009). The dysfunctional SMN2 gene and resulting lack of SMN protein are the result of alternative splicing in exon 7 of the SMN2 gene. Antisense oligonucleotides specifically targeting SMN2 transcripts can be used to induce exon 7 inclusion. Antisense applications are already being used for Duchenne dystrophy in a Phase II study (Hoffman 2007; van Deutekom 2007) but may also be promising for further research and therapeutic approaches in SMA (Hua 2007; Hua 2008). Other experimental factors Some experimental studies do not focus on the SMN gene or SMN protein. Recombinant follastatin is a natural antagonist of myostatin, which is a potent negative regulator of skeletal muscle wasting. Administration of recombinant follastatin in an SMA mouse model showed increased muscle mass in several muscle groups, elevation in the number and cross-sectional area of ventral horn cells, functional improvement and extension of survival compared to controls (Rose 2009). Until now, and despite promising results in preclinical studies or in open and uncontrolled patient trials, no drug treatment has shown a therapeutical effect in randomised placebo-controlled trials of patients with SMA. Supportive care There is a broad range of practice regarding pulmonary, nutritional, orthopedic and other forms of supportive therapy in children and adults with SMA types II and III (Wang 2007). 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). For future trials it is important that the supportive care is the same in the different treatment arms. A U T H O R S C O N C L U S I O N S Implications for practice Although some drugs looked promising in open or uncontrolled trials, the results of randomised placebo-controlled trials have been disappointing. Thus, there is still no evidence of significant efficacy for any drug treatment for SMA type II or III. 14

17 Implications for research Potential drug treatments for SMA types II and III should be sought and large randomised placebo-controlled studies are necessary to establish the efficacy of these therapies and drugs. We would foremost recommend a trial with riluzole. Drug treatment in future trials should be given for an extended period of time and patient follow-up should be sufficiently long (preferably at least one year for both treatment and follow-up). Changes in motor function, disability, muscle strength, pulmonary function and quality of life should be assessed as outcome measures and possible side effects, especially serious adverse events, should be clearly reported. Developing a new functional rating scale or choosing an existent functional rating scale as a standard scale for all trials is recommended. Also, the time from the start of treatment until death or full time ventilation should be evaluated. The (intensive) supportive care in each treatment arm should be the same. Study investigators in multicenter trials should be well trained to reliably and consistently measure muscle strength by quantitative myometry and pulmonary function in order 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 from the Cochrane Neuromuscular Disease Group was funded for the original review 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 Chen 2010 {published data only} 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: ] Mercuri 2007 {published data only} Mercuri E, Bertini E, Messina S, Solari A, D Amico A, Angelozzi C, et al.randomized, double-blind, placebocontrolled trial of phenylbutyrate in spinal muscular atrophy. Neurology 2007;68(1):51 5. [PUBMED: ] Miller 2001a {published data only} 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): [PUBMED: ] Swoboda 2010 {published data only} Swoboda KJ, Scott CB, Crawford TO, Simard LR, Reyna SP, Krosschell KJ, et al.sma CARNI-VAL trial part I: double-blind, randomized, placebo-controlled trial of L- carnitine and valproic acid in spinal muscular atrophy. PloS One 2010;5(8):e [PUBMED: ] Tzeng 2000 {published data only} Tzeng AC, Cheng J, Fryczynski H, Niranjan V, Stitik T, Sial A, et al.a study of thyrotropin-releasing hormone for the treatment of spinal muscular atrophy: a preliminary report. American Journal of Physical Medicine & Rehabilitation 2000;79(5): [PUBMED: ] Wong 2007 {published data only} 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): References to studies excluded from this review Abbara 2011 {published data only} Abbara C, Estournet B, Lacomblez L, Lelièvre B, Ouslimani A, Lehmann B, et al.riluzole pharmacokinetics in young patients with spinal muscular atrophy. British Journal of Clinical Pharmacology 2011;71(3): [PUBMED: ] Brahe 2005 {published data only} Brahe C, Vitali T, Tiziano FD, Angelozzi C, Pinto AM, Borgo F, et al.phenylbutyrate increases SMN gene expression in spinal muscular atrophy patients. European Journal of Human Genetics 2005;13(2): [PUBMED: ] 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): [PUBMED: ] 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. Folkers 1995 {published data only} Folkers K, Simonsen R. Two successful double-blind trials with coenzyme Q10 (vitamin Q10) on muscular dystrophies and neurogenic atrophies. Biochimica et Biophysica Acta 1995;1271(1): [PUBMED: ] Kato 2009 {published data only} Kato Z, Okuda M, Okumura Y, Arai T, Teramoto T, Nishimura M, et al.oral administration of the thyrotropinreleasing hormone (TRH) analogue, taltireline hydrate, in spinal muscular atrophy. Journal of Child Neurology 2009; 24(8): [PUBMED: ] 15

18 Kinali 2002 {published data only} Kinali M, Mercuri E, Main M, De Biasia F, Karatza A, Higgins R, et al.pilot trial of albuterol in spinal muscular atrophy. Neurology 2002;59(4): [PUBMED: ] Liang 2008 {published data only} Liang WC, Yuo CY, Chang JG, Chen YC, Chang YF, Wang HY, et al.the effect of hydroxyurea in spinal muscular atrophy cells and patients. Journal of the Neurological Sciences 2008;268(1-2): [PUBMED: ] Mercuri 2004 {published data only} Mercuri E, Bertini E, Messina S, Pelliccioni M, D Amico A, Colitto F, et al.pilot trial of phenylbutyrate in spinal muscular atrophy. Neuromuscular Disorders 2004;14(2): [PUBMED: ] Merlini 2003 {published data only} 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): [PUBMED: ] Nascimento 2009 {published data only} 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; Vol. 12, issue 2: [PUBMED: ] Pane 2008 {published data only} Pane M, Staccioli S, Messina S, D Amico A, Pelliccioni M, Mazzone ES, et al.daily salbutamol in young patients with SMA type II. Neuromuscular Disorders 2008;18(7): [PUBMED: ] Piepers 2010 {published data only} Piepers S, Cobben JM, Sodaar P, Jansen MD, Wadman RI, Meester-Delver A, et al.quantification of SMN protein in leucocytes from spinal muscular atrophy patients: effects of treatment with valproic acid. Journal of Neurology, Neurosurgery, and Psychiatry 2010 Jun 15. [PUBMED: ] 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: ] Tsai 2007 {published data only} Tsai LK, Yang CC, Hwu WL, Li H. Valproic acid treatment in six patients with spinal muscular atrophy. European Journal of Neurology 2007;14(12):e8 9. [PUBMED: ] Weihl 2006 {published data only} Weihl CC, Connolly AM, Pestronk A. Valproate may improve strength and function in patients with type III/ IV spinal muscle atrophy. Neurology 2006;67(3): [PUBMED: ] References to studies awaiting assessment Merlini 2007 {published data only} Merlini L, et al.european Spinal Muscular Atrophy RCT of acetyl-l-carnitine in SMA. Neuromuscular Disorders. 2007; Vol. 17: abstract no: G.P References to ongoing studies NCT {published data only} NCT Valproic acid in ambulant adults with spinal muscular atrophy (VALIANT SMA). clinicaltrials.gov/show/nct (accessed 8 August 2011). NCT {published data only} NCT Pilot study of growth hormone to treat SMA type II and III. clinicaltrials.gov/show/nct (accessed 8 August 2011). NCT {published data only} NCT A pilot therapeutic trial using hydroxyurea in type II and type III spinal muscular atrophy patients. clinicaltrials.gov/show/nct (accessed 8 August 2011). NCT {published data only} NCT Study to evaluate the efficacy of riluzole in children and young adults with spinal muscular atrophy (SMA) (ASIRI). clinicaltrials.gov/show/nct (accessed 8 August 2011). NCT {published data only} NCT Safety and efficacy of olesoxime (TRO19622) in 3-25 years SMA patients. (accessed 8 August 2011). 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): Andreassi 2004 Andreassi C, Angelozzi C, Tiziano FD, Vitali T, De Vincenzi E, Boninsegna A, et al.phenylbutyrate increases SMN expression in vitro: relevance for treatment of spinal muscular atrophy. European Journal of Human Genetics 2004;12(1): Angelini 1980 Angelini C, Micaglio GF, Trevisan C. Guanidine hydrochloride in infantile and juvenile spinal muscular atrophy. A double blind controlled study. Acta Neurologica 1980;2(6): [PUBMED: ] Angelozzi 2008 Angelozzi C, Borgo F, Tiziano FD, Martella A, Neri G, Brahe C. Salbutamol increases SMN mrna and protein 16

19 levels in spinal muscular atrophy cells. Journal of Medical Genetics 2008;45(1): Apfel 2001 Apfel SC. Neurotrophic factor therapy--prospects and problems. Clinical Chemistry and Laboratory Medicine 2001;39(4): BDNF Study Group 1999 A controlled trial of recombinant methionyl human BDNF in ALS: The BDNF Study Group (Phase III). Neurology 1999;52(7): Beck 2005 Beck M, Flachenecker P, Magnus T, Giess R, Reiners K, Toyka KV, et al.autonomic dysfunction in ALS: a preliminary study on the effects of intrathecal BDNF. Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders 2005;6(2): Bensimon 1994 Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. The New England Journal of Medicine 1994; 330(9): Bertamini 2002 Bertamini M, Marzani B, Guarneri R, Guarneri P, Bigini P, Mennini T, Curti D. Mitochondrial oxidative metabolism in motor neuron degeneration (mnd) mouse central nervous system. The European Journal of Neuroscience 2002;16(12): 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): Bessman 1981 Bessman SP, Geiger PJ. Transport of energy in muscle: the phosphorylcreatine shuttle. Science 1981;211(4481): Bigini 2002 Bigini P, Larini S, Pasquali C, Muzio V, Mennini T. Acetyl- L-carnitine shows neuroprotective and neurotrophic activity in primary culture of rat embryo motoneurons. Neuroscience Letters 2002;329(3): Bilak 2001 Bilak MM, Corse AM, Kuncl RW. Additivity and potentiation of IGF-I and GDNF in the complete rescue of postnatal motor neurons. Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders 2001;2(2): Bongioanni 2004 Bongioanni P, Reali C, Sogos V. Ciliary neurotrophic factor (CNTF) for amyotrophic lateral sclerosis or motor neuron disease. Cochrane Database of Systematic Reviews 2004, Issue 3. [DOI: / CD pub2] Bordet 2001 Bordet T, Lesbordes JC, Rouhani S, Castelnau-Ptakhine L, Schmalbruch H, Haase G, et al.protective effects of cardiotrophin-1 adenoviral gene transfer on neuromuscular degeneration in transgenic ALS mice. Human Molecular Genetics 2001;10(18): Bordet 2008 Bordet T, Buisson B, Michaud M, Abitbol JL, Marchand F, Grist J, et al.specific antinociceptive activity of cholest-4- en-3-one, oxime (TRO19622) in experimental models of painful diabetic and chemotherapy-induced neuropathy. The Journal of Pharmacology and Experimental Therapeutics 2008;326(2): [PUBMED: ] Bradley 1990 Bradley WG. Critical review of gangliosides and thyrotropin-releasing hormone in peripheral neuromuscular diseases. Muscle & Nerve 1990;13(9): 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: ] Bresolin 1984 Bresolin N, Freddo L, Tegazzin V, Bet L, Armani M, Angelini C. Carnitine and acyltransferase in experimental neurogenic atrophies: changes with treatment. Journal of Neurology 1984;231(4): Brichta 2003 Brichta L, Hofmann Y, Hahnen E, Siebzehnrubl FA, Raschke H, Blumcke I, et al.valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophy. Human Molecular Genetics 2003;12(19): Brooke 1986 Brooke MH, Florence JM, Heller SL, Kaiser KK, Phillips D, Gruber A, et al.controlled trial of thyrotropin releasing hormone in amyotrophic lateral sclerosis. Neurology 1986; 36(2): Brooke 1989 Brooke MH. Thyrotropin-releasing hormone in ALS. Are the results of clinical studies inconsistent?. Annals of the New York Academy of Sciences 1989;553: 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): Butchbach 2010 Butchbach ME, Singh J, Thorsteinsdottir M, Saieva L, Slominski E, Thurmond J, et al.effects of 2,4- diaminoquinazoline derivatives on SMN expression and phenotype in a mouse model for spinal muscular atrophy. Human Molecular Genetics 2010;19(3): [PUBMED: ] 17

20 Cabanes 2007 Cabanes C, Bonilla S, Tabares L, Martinez S. Neuroprotective effect of adult hematopoietic stem cells in a mouse model of motoneuron degeneration. Neurobiology of Disease 2007;26(2): Caroscio 1986 Caroscio JT, Cohen JA, Zawodniak J, Takai V, Shapiro A, Blaustein S, et al.a double-blind, placebo-controlled trial of TRH in amyotrophic lateral sclerosis. Neurology 1986;36 (2): 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): Caruso 1995 Caruso JF, Signorile JF, Perry AC, Leblanc B, Williams R, Clark M, et al.the effects of albuterol and isokinetic exercise on the quadriceps muscle group. Medicine and Science in Sports and Exercise 1995;27(11): Cifuentes-Diaz 2002 Cifuentes-Diaz C, Nicole S, Velasco ME, Borra-Cebrian C, Panozzo C, Frugier T, et al.neurofilament accumulation at the motor endplate and lack of axonal sprouting in a spinal muscular atrophy mouse model. Human Molecular Genetics 2002;11(12): [PUBMED: ] Cobben 1995 Cobben JM, van der Steege G, 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): Darras 2007 Darras BT, Kang PB. Clinical trials in spinal muscular atrophy. Current Opinion in Pediatrics 2007;19(6): Dayangac-Erden 2009 Dayangac-Erden D, Bora G, Ayhan P, Kocaefe C, Dalkara S, Yelekci K, et al.histone deacetylase inhibition activity and molecular docking of (e )-resveratrol: its therapeutic potential in spinal muscular atrophy. Chemical Biology & Drug Design 2009;73(3): [PUBMED: ] Desnuelle 2001 Desnuelle C, Dib M, Garrel C, Favier A. A double-blind, placebo-controlled randomized clinical trial of alphatocopherol (vitamin E) in the treatment of amyotrophic lateral sclerosis. ALS riluzole-tocopherol Study Group. Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders 2001;2(1):9 18. 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): Ellis 2004 Ellis AC, Rosenfeld J. The role of creatine in the management of amyotrophic lateral sclerosis and other neurodegenerative disorders. CNS Drugs 2004;18(14): 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): Franz 1995 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. 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): Gibal 1997 Gibal BE, Inglese CM, Meyer JF, Pitterle ME, Antonopolous J, Rust RS. Diet- and valproate-induced transient hyperammonemia: effect of L-carnitine. Pediatric Neurology 1997;16(4): Gilliam 1990 Gilliam TC, Brzustowicz LM, Castilla LH, Lehner T, Penchaszadeh GK, Daniels RJ, et al.genetic homogeneity between acute and chronic forms of spinal muscular atrophy. Nature 1990;345(6278):

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