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Meta-Analysis
. 2020 Jan 6;1(1):CD006282.
doi: 10.1002/14651858.CD006282.pub5.

Drug treatment for spinal muscular atrophy types II and III

Renske I Wadman  1 , W Ludo van der Pol  1 , Wendy Mj Bosboom  2 , Fay-Lynn Asselman  1 , Leonard H van den Berg  1 , Susan T Iannaccone  3 , Alexander Fje Vrancken  1
Affiliations
Meta-Analysis

Drug treatment for spinal muscular atrophy types II and III

Renske I Wadman et al. Cochrane Database Syst Rev. .

Abstract

Background: Spinal muscular atrophy (SMA) is caused by a homozygous deletion of the survival motor neuron 1 (SMN1) gene on chromosome 5, or a heterozygous deletion in combination with a (point) mutation in the second SMN1 allele. This results in 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. This is an update of a review first published in 2009 and previously updated in 2011.

Objectives: To evaluate if 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.

Search methods: We searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and ISI Web of Science conference proceedings in October 2018. In October 2018, we also searched two trials registries to identify unpublished trials.

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 homozygous deletion or hemizygous deletion in combination with a point mutation in the second allele of the SMN1 gene (5q11.2-13.2) confirmed by genetic analysis. The primary outcome measure was change in disability score within one year after the onset of treatment. Secondary outcome measures within one year after the onset of treatment were 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. Treatment strategies involving SMN1-replacement with viral vectors are out of the scope of this review, but a summary is given in Appendix 1. Drug treatment for SMA type I is the topic of a separate Cochrane Review.

Data collection and analysis: We followed standard Cochrane methodology.

Main results: The review authors found 10 randomised, placebo-controlled trials of treatments for SMA types II and III for inclusion in this review, with 717 participants. We added four of the trials at this update. The trials investigated creatine (55 participants), gabapentin (84 participants), hydroxyurea (57 participants), nusinersen (126 participants), olesoxime (165 participants), phenylbutyrate (107 participants), somatotropin (20 participants), thyrotropin-releasing hormone (TRH) (nine participants), valproic acid (33 participants), and combination therapy with valproic acid and acetyl-L-carnitine (ALC) (61 participants). Treatment duration was from three to 24 months. None of the studies investigated the same treatment and none was completely free of bias. All studies had adequate blinding, sequence generation and reporting of primary outcomes. Based on moderate-certainty evidence, intrathecal nusinersen improved motor function (disability) in children with SMA type II, with a 3.7-point improvement in the nusinersen group on the Hammersmith Functional Motor Scale Expanded (HFMSE; range of possible scores 0 to 66), compared to a 1.9-point decline on the HFMSE in the sham procedure group (P < 0.01; n = 126). On all motor function scales used, higher scores indicate better function. Based on moderate-certainty evidence from two studies, the following interventions had no clinically important effect on motor function scores in SMA types II or III (or both) in comparison to placebo: creatine (median change 1 higher, 95% confidence interval (CI) -1 to 2; on the Gross Motor Function Measure (GMFM), scale 0 to 264; n = 40); and combination therapy with valproic acid and carnitine (mean difference (MD) 0.64, 95% CI -1.1 to 2.38; on the Modified Hammersmith Functional Motor Scale (MHFMS), scale 0 to 40; n = 61). Based on low-certainty evidence from other single studies, the following interventions had no clinically important effect on motor function scores in SMA types II or III (or both) in comparison to placebo: gabapentin (median change 0 in the gabapentin group and -2 in the placebo group on the SMA Functional Rating Scale (SMAFRS), scale 0 to 50; n = 66); hydroxyurea (MD -1.88, 95% CI -3.89 to 0.13 on the GMFM, scale 0 to 264; n = 57), phenylbutyrate (MD -0.13, 95% CI -0.84 to 0.58 on the Hammersmith Functional Motor Scale (HFMS) scale 0 to 40; n = 90) and monotherapy of valproic acid (MD 0.06, 95% CI -1.32 to 1.44 on SMAFRS, scale 0 to 50; n = 31). Very low-certainty evidence suggested that the following interventions had little or no effect on motor function: olesoxime (MD 2, 95% -0.25 to 4.25 on the Motor Function Measure (MFM) D1 + D2, scale 0 to 75; n = 160) and somatotropin (median change at 3 months 0.25 higher, 95% CI -1 to 2.5 on the HFMSE, scale 0 to 66; n = 19). One small TRH trial did not report effects on motor function and the certainty of evidence for other outcomes from this trial were low or very low. Results of nine completed trials investigating 4-aminopyridine, acetyl-L-carnitine, CK-2127107, hydroxyurea, pyridostigmine, riluzole, RO6885247/RG7800, salbutamol and valproic acid were awaited and not available for analysis at the time of writing. Various trials and studies investigating treatment strategies other than nusinersen (e.g. SMN2-augmentation by small molecules), are currently ongoing.

Authors' conclusions: Nusinersen improves motor function in SMA type II, based on moderate-certainty evidence. Creatine, gabapentin, hydroxyurea, phenylbutyrate, valproic acid and the combination of valproic acid and ALC probably have no clinically important effect on motor function in SMA types II or III (or both) based on low-certainty evidence, and olesoxime and somatropin may also have little to no clinically important effect but evidence was of very low-certainty. One trial of TRH did not measure motor function.

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Conflict of interest statement

RW: was involved as investigator at a participating centre in the trials on the safety and efficacy of cholest‐4‐en‐3‐one, oxime for children with SMA types II and IIIa (Bertini 2017; OLEOS), and is involved as an investigator in the monocentre placebo‐controlled trial of pyridostigmine in children and adults with SMA types II to IV (SPACE). She does not receive any funding from the pharmaceutical industry.

WP: receives research support from the Prinses Beatrix Spierfonds, Stichting Spieren voor Spieren, Netherlands ALS foundation. His employer receives fees for consultancy services to Biogen, Avexis and Novartis. WP was an investigator at a participating centre in the trials on the safety and efficacy of cholest‐4‐en‐3‐one, oxime for children with SMA types II and IIIa (Bertini 2017; OLEOS), and is an investigator in the monocentre placebo‐controlled trial of pyridostigmine in children and adults with SMA types II to IV (SPACE).

WB: none.

FA: none.

LB: serves on scientific advisory boards for the Prinses Beatrix Spierfonds, Thierry Latran Foundation, Biogen Idec and Cytokinetics; received an educational grant from Baxter International Inc; serves on the editorial board of Amyotrophic Lateral Sclerosis and the Journal of Neurology, Neurosurgery and Psychiatry; and receives research support from the Prinses Beatrix Fonds, Netherlands ALS Foundation, The European Community's Health Seventh Framework Programme (grant agreement number 259867), and The Netherlands Organization for Health Research and Development (Vici Scheme, JPND (SOPHIA, STRENGTH)). LB was an investigator at a participating centre in the trials on the safety and efficacy of cholest‐4‐en‐3‐one, oxime for children with SMA types II and IIIa (Bertini 2017; OLEOS) and is an investigator of the monocentre placebo‐controlled trial on pyridostigmine in children and adults with SMA types II to IV (SPACE).

SI: Dr Iannaccone was involved in the trial of riluzole as one of the investigators and authors (Russman 2003). She was involved in a trial of the efficacy of creatine for children with spinal muscular atrophy types II and III as investigator and author (Wong 2007) and she was involved in a trial of the efficacy of riluzole (not published). She has received support for research from AveXis, Biogen and Scholar Rock for clinical trials in SMA patients and from Sarepta, Reveragen, Mallinckrodt, Fibrogen, and PTC Therapeutics for clinical trials in muscular dystrophy. She has been a consultant for AveXis, Biogen, Sarepta, Audentes, Catabasis and Genentech/Roche.

AV: none known. He was involved as investigators at a participating centre in the trials on the safety and efficacy of cholest‐4‐en‐3‐one, oxime for children with SMA types II and IIIa (Bertini 2017; OLEOS), and is an investigator in the monocentre placebo‐controlled trial of pyridostigmine in children and adults with SMA types II to IV (SPACE).

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all 10 included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
See this image and copyright information in PMC

Update of

References

References to studies included in this review

Bertini 2017 {published data only}
    1. Bertini E, Dessaud E, Mercuri E, Muntoni F, Kirschner J, Reid C, et al. Safety and efficacy of olesoxime in patients with type 2 or non‐ambulatory type 3 spinal muscular atrophy: a randomised, double‐blind, placebo‐controlled phase 2 trial. Lancet Neurology 2017;16(7):513‐22. Corrections in Lancet Neurology 2017; 16(8):584. [DOI: 10.1016/S1474-4422(17)30085-6; 3134415] - DOI - PubMed
    1. NCT01302600. Safety and efficacy of olesoxime (TRO19622) in 3‐25 years SMA patients. clinicaltrials.gov/ct2/show/NCT01302600 (first received 24 February 2011).
Chen 2010 {published data only}
    1. 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):2190‐7. [PUBMED: 21172842] - PubMed
    1. NCT00485511. A trial of hydroxyurea in spinal muscular atrophy. clinicaltrials.gov/ct2/show/NCT00485511 (first received 13 June 2007).
Kirschner 2014 {published data only}
    1. Kirschner J, Schorling D, Hauschke D, Rensing‐Zimmermann C, Wein U, Grieben U, et al. Somatropin treatment of spinal muscular atrophy: a placebo‐controlled, double‐blind crossover pilot study. Neuromuscular Disorders 2014;24(2):134‐42. [PUBMED: 24300782] - PubMed
    1. NCT00533221. Pilot study of growth hormone to treat SMA type II and III. clinicaltrials.gov/ct2/show/NCT00533221 (first received 21 September 2007).
Kissel 2014 {published data only}
    1. Kissel JT, Elsheikh B, King WM, Freimer M, Scott CB, Kolb SJ, et al. SMA valiant trial: a prospective, double‐blind, placebo‐controlled trial of valproic acid in ambulatory adults with spinal muscular atrophy. Muscle & Nerve 2014;49(2):187‐92. [PUBMED: 23681940] - PMC - PubMed
    1. NCT00481013. Valproic acid in ambulant adults with spinal muscular atrophy (VALIANTSMA). clinicaltrials.gov/ct2/show/NCT00481013.
Mercuri 2007 {published data only}
    1. Mercuri E, Bertini E, Messina S, Solari A, D'Amico A, Angelozzi C, et al. Randomized, double‐blind, placebo‐controlled trial of phenylbutyrate in spinal muscular atrophy. Neurology 2007;68(1):51‐5. [PUBMED: 17082463] - PubMed
Mercuri 2018 (CHERISH) {published data only}
    1. Mercuri E, Darras BT, Chiriboga CA, Day JW, Campbell C, Connolly AM, et al. Nusinersen versus sham control in later‐onset spinal muscular atrophy. New England Journal of Medicine 2018;378(7):625‐35. [IONIS 396443‐CS4] - PubMed
    1. NCT02292537. A study to assess the efficacy and safety of nusinersen (ISIS 396443) in participants with later‐onset spinal muscular atrophy (SMA) (CHERISH). clinicaltrials.gov/ct2/show/NCT02292537 (first received 17 November 2014).
Miller 2001 {published data only}
    1. 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):127‐31. [PUBMED: 11677003] - PubMed
Swoboda 2010 {published data only}
    1. NCT00227266. Valproic acid and carnitine in patients with spinal muscular atrophy. clinicaltrials.gov/ct2/show/study/NCT00227266 (first received 27 September 2005).
    1. 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):e12140. [PUBMED: 20808854] - PMC - PubMed
Tzeng 2000 {published data only}
    1. 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):435‐40. [PUBMED: 10994885] - PubMed
Wong 2007 {published data only}
    1. 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):101‐10. [EMBASE: 46673514]

References to studies excluded from this review

Abbara 2011 {published data only}
    1. 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):403‐10. [PUBMED: 21284699] - PMC - PubMed
Brahe 2005 {published data only}
    1. 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):256‐9. [PUBMED: 15523494] - PubMed
Brichta 2006 {published data only}
    1. 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):970‐5. [PUBMED: 16607616] - PubMed
Chang 2002 {published data only}
    1. Chang JG, Tsai FJ, Wang WY, Jong YJ. Treatment of spinal muscular atrophy by hydroxyurea. American Journal of Human Genetics 2002; Vol. 71 Suppl 4:2402.
Chiriboga 2016 {published data only}
    1. Chiriboga CA, Swoboda KJ, Darras BT, Iannaccone ST, Montes J, Vivo DC, et al. Results from a phase 1 study of nusinersen (ISIS‐SMNRx) in children with spinal muscular atrophy. Neurology 2016;86(10):890‐7. [ISIS 396443 ‐ CS1; ISIS 396443 ‐ CS10; NCT01494701; NCT01780246] - PMC - PubMed
Darbar 2011 {published data only}
    1. Darbar IA, Plaggert PG, Resende MBD, Zanotelli E, Reed UC. Evaluation of muscle strength and motor abilities in children with type II and III spinal muscle atrophy treated with valproic acid. BMC Neurology 2011;11:36. [PUBMED: 21435220] - PMC - PubMed
EMOTAS 2014 {unpublished data only}
    1. NCT02227823. Safety and efficacy study of pyridostigmine on patients with spinal muscular atrophy type 3. www.clinicaltrials.gov/show/NCT02227823 (first received 20 August 2014). [1376 ; NCT02227823]
Folkers 1995 {published data only}
    1. 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):281‐6. [PUBMED: 7599221] - PubMed
Giovannetti 2016 {published data only}
    1. Giovannetti AM, Pasanisi MB, Černiauskaitė M, Bussolino C, Leonardi M, Morandi L. Perceived efficacy of salbutamol by persons with spinal muscular atrophy: a mixed methods study. Muscle & Nerve 2016;54(5):843‐9. - PubMed
    1. Pasanisi MB, Giovannetti AM, Bussolino C, Campanella A, Leonardi M, Morandi L. Perception of efficacy in adult patients affected by spinal muscular atrophy (SMA) treated with salbutamol. Neuromuscular Disorders 2014;24(9‐10):914.
JEWELFISH 2017 {unpublished data only}
    1. NCT03032172. A study of RO7034067 in adult and pediatric participants with spinal muscular atrophy (Jewelfish). clinicaltrials.gov/show/NCT03032172 (first received 24 January 2017).
JPRN‐JapicCTI‐163450 2016 {unpublished data only}
    1. JPRN‐JapicCTI‐163450. Phase 3 study of K‐828‐SP. apps.who.int/trialsearch/Trial2.aspx?TrialID=JPRN‐JapicCTI‐163450 (first received November 2016).
Kato 2009 {published data only}
    1. Kato Z, Okuda M, Okumura Y, Arai T, Teramoto T, Nishimura M, et al. Oral administration of the thyrotropin‐releasing hormone (TRH) analogue, taltireline hydrate, in spinal muscular atrophy. Journal of Child Neurology 2009;24(8):1010‐2. [PUBMED: 19666885] - PubMed
Khirani 2017 {published data only}
    1. Khirani S, Dabaj I, Amaddeo A, Olmo Arroyo J, Ropers J, Tirolien S, et al. Effect of salbutamol on respiratory muscle strength in spinal muscular atrophy. Pediatric Neurology 2017;73:78‐87. - PubMed
Kinali 2002 {published data only}
    1. Kinali M, Mercuri E, Main M, Biasia F, Karatza A, Higgins R, et al. Pilot trial of albuterol in spinal muscular atrophy. Neurology 2002;59(4):609‐10. [PUBMED: 12196659] - PubMed
Kissel 2011 {published data only}
    1. Kissel JT, Scott CB, Reyna SP, Crawford TO, Simard LR, Krosschell KJ, et al. SMA CARNIVAL trial part II: a prospective, single‐armed trial of L‐carnitine and valproic acid in ambulatory children with spinal muscular atrophy. PloS One 2011;6(7):e21296. [PUBMED: 21754985] - PMC - PubMed
Liang 2008 {published data only}
    1. 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):87‐94. [PUBMED: 18166199] - PubMed
Mercuri 2004 {published data only}
    1. 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):130‐5. [PUBMED: 14733959] - PubMed
Merlini 2003 {published data only}
    1. 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):537‐41. [PUBMED: 13677579] - PubMed
Nascimento 2010 {published data only}
    1. Nascimento OJ, Orsini M, Quintanilha G. Lamotrigine on motor symptoms of spinal muscular atrophies. Revista de Neurologia 2010;50(2):127‐8. [PUBMED: 20112222] - PubMed
NCT01703988 {unpublished data only}
    1. Darras BT, Chiriboga C, Swoboda K, Iannaccone S, Montes J, Rausch N, et al. Results of a first‐in‐human phase I study to assess the safety, tolerability, and dose range finding of a single intrathecal dose of ISIS‐SMNRx in patients with spinal muscular atrophy. Annals of Neurology 2013;74 Suppl 17:S128.
    1. NCT01703988. An open‐label safety, tolerability and dose‐range finding study of multiple doses of ISIS SMNRx in patients with spinal muscular atrophy (SMNRx ‐ CS2). clinicaltrials.gov/show/NCT01703988 (first received 8 October 2012). [IONIS SMNRx‐CS2 ; NCT01703988]
NCT02052791 {unpublished data only}
    1. NCT02052791. An open‐label safety and tolerability study of IONIS SMNRx in patients with spinal muscular atrophy who previously participated in IONIS SMNRx‐CS2 or IONIS SMNRx‐CS10. www.clinicaltrials.gov/show/NCT02052791 (first received 30 January 2014). [IONIS SMNRx‐CS12 ; ISIS 396443‐CS12 ; NCT02052791]
NCT02876094 {unpublished data only}
    1. NCT02876094. Effect of low‐dose celecoxib on SMN2 in patients with spinal muscular atrophy (SMA). www.clinicaltrials.gov/show/NCT02876094 (first received 9 August 2016). [NCT02876094]
NCT03709784 {unpublished data only}
    1. NCT03709784. Spinraza in adult spinal muscular atrophy (SAS). clinicaltrials.gov/ct2/show/NCT03709784 (first received 17 October 2018).
NPTUNE01 2007 {unpublished data only}
    1. NCT00439569. Clinical trial of sodium phenylbutyrate in children with spinal muscular atrophy types II or III. clinicaltrials.gov/show/NCT00439569 (first received 21 February 2007). [HHSN265200423611C; N01NS42361_NPTUNE01; NCT00439569; NPTUNE01]
OLEOS {unpublished data only}
    1. NCT02628743. A study to evaluate long term safety, tolerability, and effectiveness of olesoxime in patients with spinal muscular atrophy. clinicaltrials.gov/show/NCT02628743 (first received 1 December 2015). [2015‐001589‐25; BN29854 ; EUCTR2015‐001589‐25‐GB; NCT02628743]
Pane 2008 {published data only}
    1. 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):536‐40. [PUBMED: 18579379] - PubMed
Piepers 2011 {published data only}
    1. 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 2011;82(8):850‐2. [PUBMED: 20551479] - PubMed
Prufer de Queiroz Campos Araujo 2010 {published data only}
    1. Prufer de Queiroz Campos Araujo A. Long‐term open salbutamol trial in spinal muscular atrophy. Journal of Neurology 2010;257 (Suppl 1):S101. [PUBMED: 20495927]
Saito 2014 {published data only}
    1. Saito T, Nurputra DK, Harahap NI, Harahap IS, Yamamoto H, Muneshige E, et al. A study of valproic acid for patients with spinal muscular atrophy. Neurology and Clinical Neuroscience 2014;3:49‐57.
SHINE 2015 {unpublished data only}
    1. NCT02594124. An open‐label study (SHINE) for patients with spinal muscular atrophy (SMA) who participated in studies with IONIS‐SMNRx. clinicaltrials.gov/show/NCT02594124 (first received 30 October 2015). [EUCTR2015‐001870‐16‐DE; IONIS SMNRx‐CS11; ISIS 396443‐CS11 ; NCT02594124]
SMART01 {unpublished data only}
    1. SMART01. Multicenter cooperative and investigator initiated clinical trial using valproic acid in childhood onset spinal muscular atrophy. dbcentre3.jmacct.med.or.jp/jmactr/App/JMACTRE02_04/JMACTRE02_04.aspx?kbn... (first received August 2014). [JPRN‐SMA‐IIA00190]
SMART03 {unpublished data only}
    1. SMART03. Multicenter cooperative and investigator initiated clinical trial using valproic acid in childhood onset spinal muscular atrophy: continuous administration trial. dbcentre3.jmacct.med.or.jp/jmactr/App/JMACTRE02_04/JMACTRE02_04.aspx?kbn... (first received August 2016).
Swoboda 2009 {published data only}
    1. 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: 19440247] - PMC - PubMed
Tan 2011 {published data only}
    1. Tan C, Williams AN. Oral salbutamol in 2 wheelchair bound cases of SMA type II. Archives of Disease in Childhood 2011;96 Suppl 1:G77(P).
Tsai 2007 {published data only}
    1. 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: 18028187] - PubMed
Weihl 2006 {published data only}
    1. 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):500‐1. [PUBMED: 16775228] - PubMed

References to studies awaiting assessment

ASIRI 2008 {unpublished data only}
    1. NCT00774423. Study to evaluate the efficacy of riluzole in children and young adults with spinal muscular atrophy (SMA) (ASIRI). clinicaltrials.gov/show/NCT00774423 (first received 16 October 2008). [NCT00774423; P040904]
CHICTR‐TRC‐10001093 {unpublished data only}
    1. CHICTR‐TRC‐10001093. Rat nerve growth factor injection in the treatment of children with spinal muscular atrophy: a randomized controlled trial. www.chictr.org.cn/showprojen.aspx?proj=8445 (first received 11 February 2010). [ChiCTR‐TRC‐10001093]
Merlini 2007 {published data only}
    1. Merlini L, Basoglu B, Dohna‐Schwake C, Febrer A, Hausmanova‐Petrusewicz I, Jedrzejowska M, et al. European spinal muscular atrophy RCT of acetyl‐L‐carnitine in SMA. Neuromuscular Disorders 2007;17:780‐1.
MOONFISH 2014 {unpublished data only}
    1. NCT02240355. A study of RO6885247 in adult and pediatric patients with spinal muscular atrophy (MOONFISH). clinicaltrials.gov/show/NCT02240355 (first received 11 September 2014). [2014‐002246‐41; BP29420 ; NCT02240355]
Morandi 2013 {published data only}
    1. Morandi L, Abiusi E, Pasanisi MB, Lomastro R, Fiori S, Pietro L, et al. Salbutamol tolerability and efficacy in adult type III SMA patients: results of a multicentric, molecular and clinical, double‐blind, placebo‐controlled study. Neuromuscular Disorders 2013;9(10):771.
    1. Tiziano FD, Lomastro R, Pietro L, Pasanisi MB, Fiori S, Angelozzi C, et al. Phase‐ll multicenter double‐blind, placebo‐controlled study of tolerability and efficacy of salbutamol in adult type III SMA patients. Acta Myologica 2012;31:97.
NCT00568802 {unpublished data only}
    1. NCT00568802. A pilot therapeutic trial using hydroxyurea in type II and type III spinal muscular atrophy patients. clinicaltrials.gov/show/NCT00568802 (first received 4 December 2007). [NCT00084006; NCT00568802; SU‐11012007‐781 79233]
NCT01645787 {unpublished data only}
    1. NCT01645787. Short and long term treatment with 4‐AP in ambulatory SMA patients. clinicaltrials.gov/show/NCT01645787 (first received 5 July 2012). [AAAI7400 ; NCT01645787]
NCT02644668 {unpublished data only}
    1. NCT02644668. A study of CK‐2127107 in patients with spinal muscular atrophy. clinicaltrials.gov/show/NCT02644668 (first received 23 December 2015). [CY 5021; NCT02644668]
    1. Rudnicki S, Andrews J, Malik F, Wolff A, Day J. CK‐2127107 a selective activator of the fast skeletal muscle troponin complex, for the potential treatment of spinal muscular atrophy. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 2016;17(Suppl 1):P261.
SPACE {unpublished data only}
    1. SPACE. SPACE trial SMA and pyridostigmine in adults and children; experimental trial to assess effect of pyridostigmine compared to placebo in patients with spinal muscular atrophy types 2, 3 and 4. apps.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2011‐004369‐34‐NL (first received October 2016). [EUCTR2011‐004369‐34‐NL]

References to ongoing studies

EMBRACE 2015 {published data only}
    1. NCT02462759. A study to assess the safety and tolerability of ISIS 396443 (IONIS SMNRx) in participants with spinal muscular atrophy (SMA) (EMBRACE). clinicaltrials.gov/show/NCT02462759 (first received 14 May 2015). [232SM202 ; EUCTR2014‐003657‐33‐DE; NCT02462759]
NCT01671384 {published data only}
    1. NCT01671384. Valproate and levocarnitine in children with spinal muscular atrophy. clinicaltrials.gov/show/NCT01671384 (first received 13 August 2012). [NCT01671384]
SMART02 {unpublished data only}
    1. SMART02. Multicenter cooperative and investigator initiated clinical trial using valproic acid in childhood onset spinal muscular atrophy: confirmatory trial. dbcentre3.jmacct.med.or.jp/JMACTR/App/JMACTRS06/JMACTRS06.aspx?seqno=5544 (first received 12 January 2016). [27‐3594; JPRN‐JMA‐IIA00231]
SUNFISH 2016 {unpublished data only}
    1. SUNFISH. A study to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of RO7034067 in type 2 and 3 spinal muscular atrophy participants (Sunfish). clinicaltrials.gov/show/NCT02908685 (first received 19 September 2016).

Additional references

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References to other published versions of this review

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