1. No category

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
http://www.thecochranelibrary.com
Drug treatment for spinal muscular atrophy types II and III (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . .
ABSTRACT . . . . . . . . . . . . . . . . .
PLAIN LANGUAGE SUMMARY . . . . . . . . .
BACKGROUND . . . . . . . . . . . . . . .
OBJECTIVES . . . . . . . . . . . . . . . .
METHODS . . . . . . . . . . . . . . . . .
RESULTS . . . . . . . . . . . . . . . . . .
Figure 1.
. . . . . . . . . . . . . . . .
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
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Drug treatment for spinal muscular atrophy types II and III (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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i
[Intervention Review]
Drug treatment for spinal muscular atrophy types II and III
Renske I Wadman1 , Wendy MJ Bosboom2 , W Ludo van der Pol1 , Leonard H van den Berg1 , John HJ Wokke1 , Susan T Iannaccone
3
, Alexander FJE Vrancken1
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. [email protected].
Editorial group: Cochrane Neuromuscular Disease Group.
Publication status and date: Edited (no change to conclusions), published in Issue 4, 2012.
Review content assessed as up-to-date: 8 March 2011.
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.: CD006282.
DOI: 10.1002/14651858.CD006282.pub4.
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ABSTRACT
Background
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 2009.
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 8 2011). 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 (5q11.2-13.2) 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.
Drug treatment for spinal muscular atrophy types II and III (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
1
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.
PLAIN LANGUAGE SUMMARY
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.
BACKGROUND
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-
Drug treatment for spinal muscular atrophy types II and III (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
2
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, WohlfartKugelberg-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 5q11.2-13.3
(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
Drug treatment for spinal muscular atrophy types II and III (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
3
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 2009. Drug treatment for
SMA type I is the subject of a separate Cochrane review (Wadman
2011).
OBJECTIVES
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.
METHODS
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.
Types of participants
Children or adolescents with SMA types II and III fulfilling the
criteria outlined in Table 1.
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.
Search methods for identification of studies
Electronic searches
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.
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.
Drug treatment for spinal muscular atrophy types II and III (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
4
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.
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 Chi2 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.
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
RESULTS
Drug treatment for spinal muscular atrophy types II and III (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
5
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), EMBASE 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
Mercuri 2007
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
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
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6
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
TM
) 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 PedsQLT 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-
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7
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.
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Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
8
Figure 1. Risk of bias summary: review authors’ judgements about each risk of bias item for each included
study.
Drug treatment for spinal muscular atrophy types II and III (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
9
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.
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10
(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).
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
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.
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
DISCUSSION
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).
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11
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
(NCT00439569). 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
NCT00528268).
(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 (NCT00481013). 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 (NCT00227266).
Hydroxyurea
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
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 (NCT00568802).
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
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Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
12
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.
controlled 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
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 placebo-
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
(NCT00774423).
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 1991. 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 730
Drug treatment for spinal muscular atrophy types II and III (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
13
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 (NCT00533221). 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 (NCT00496457). A pivotal 18-month ALS European multicenter study was initiated in April 2009 and is still ongoing
(NCT00868166 ). 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 (NCT01302600).
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).
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.
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
AUTHORS’ CONCLUSIONS
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.
Drug treatment for spinal muscular atrophy types II and III (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
14
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.
ACKNOWLEDGEMENTS
Editorial support from the Cochrane Neuromuscular Disease
Group was funded for the original review by the TREAT NMD
European Union Grant 036825. The Cochrane Neuromuscular
Disease Group editorial base is supported by the MRC Centre for
Neuromuscular Disease and the Muscular Dystrophy Campaign.
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∗
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Indicates the major publication for the study
Drug treatment for spinal muscular atrophy types II and III (Review)
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24
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Chen 2010
Methods
Randomised, placebo-controlled double-blind trial
Participants
57 patients above 5 years old who fulfilled international classification criteria for SMA
types II or III and with a homozygous deletion of the SMN1 gene
Interventions
Oral hydroxyurea in escalating dose from 10 mg/kg to 20 mg/kg over 8 weeks (5 mg/kg
increase per 4 weeks) or placebo in increasing dose over 8 weeks. Duration of treatment
18 months, follow-up time 6 months post-treatment
Outcomes
Change in functional score (GMFM), change in functional score in non-ambulatory
patients (HMFS), change in muscle strength (MMT), change in pulmonary function
(FVC), adverse events
Notes
Randomisation procedures were not clear
GMFM = Gross Motor Function Manual; HFMS = Hammersmith Funtional Motor
Scale; MMT = Manual Muscle Testing; FVC = forced vital capacity
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection Low risk
bias)
Randomly assigned
Allocation concealment (selection bias)
No details of randomisation were given
Unclear risk
Blinding (performance bias and detection Low risk
bias)
All outcomes
Patients, families, investigators, study coordinators, evaluators and statisticians were
blinded Randomisation unit and study
pharmacist were not blinded
Incomplete outcome data (attrition bias)
All outcomes
Low risk
No missing outcome data
Selective reporting (reporting bias)
Low risk
Adequate
Other bias
Unclear risk
Discrepancy in results of respiratory failure
(results in text and figures appear to be different)
Drug treatment for spinal muscular atrophy types II and III (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
25
Mercuri 2007
Methods
Randomised, placebo-controlled, double-blind trial
Participants
107 patients who fulfilled international classification criteria for SMA type II and have
a homozygous deletion of the SMN1 gene
Interventions
Phenylbutyrate 500 mg/kg/d 7 days orally, divided in 5 doses using an intermittent
schedule (7 days on/7 days off ) or placebo. Duration of treatment 3 months, follow-up
3 months
Outcomes
Functional score (HFMS), change in functional score. Subgroup above 5 years: change in
muscle strength arm and leg (myometry), change in pulmonary function (FVC), adverse
events
Notes
Muscle strength was measured bilaterally for elbow flexion, hand grip, and three point
pinch. Muscle strength was measured bilaterally for knee flexion and knee extension
HFMS = Hammersmith functional motor scale; FVC = forced vital capacity
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection Low risk
bias)
Randomly assigned
Allocation concealment (selection bias)
Central allocation. Method of randomisation not known
Unclear risk
Blinding (performance bias and detection Low risk
bias)
All outcomes
Only randomisation unit and pharmacy
had access to assignment
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk
Myometry and FVC were measured in children above the age of 5 years, but a different number of children are reported in the
2 groups. No report on explaining this difference
Selective reporting (reporting bias)
Low risk
Adequate
Other bias
Unclear risk
Medication provided by pharmaceutical
company, but no details about the involvement of the company in study procedures
Drug treatment for spinal muscular atrophy types II and III (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
26
Miller 2001a
Methods
Randomised, placebo-controlled, double-blind trial (2 x 2 block design)
Participants
84 patients who fulfilled international classification criteria for SMA type II or III and
have a homozygous deletion of the SMN1 gene
Interventions
Gabapentin 1200 mg three times a day or placebo. Duration of treatment 12 months;
follow-up at quarterly time intervals while on treatment
Outcomes
Change in disability score (SMAFRS), change in muscle strength, development of walking, change in pulmonary function (FVC), change in quality of life (SIP), adverse events
Notes
Muscle strength of elbow flexion and hand grip was measured bilaterally
SMAFRS = spinal muscular atrophy functional rating scale; FVC = forced vital capacity;
SIP = sickness impact profile
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection Low risk
bias)
Randomly assigned
Allocation concealment (selection bias)
Randomisation performed by research
pharmacist. Randomisation in blocks of
4 patients (2 placebo, 2 gabapentin) with
equalised randomisation per center. Precise
method of allocation not known
Unclear risk
Blinding (performance bias and detection Low risk
bias)
All outcomes
Only research pharmacist was not blinded
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk
Drop-out reasons not mentioned
Selective reporting (reporting bias)
Low risk
All outcome measures are mentioned adequately as well as possible biases
Other bias
Unclear risk
Intention-to-treat analysis performed with
a different number of patients then initially
included
Randomisation per site (2 by 2)
Drug treatment for spinal muscular atrophy types II and III (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
27
Swoboda 2010
Methods
Randomised, placebo-controlled, double-blind trial
Participants
61 non-ambulatory patients with SMA types II or III between 2 to 8 years old with
confirmed genetic diagnosis of SMA
Interventions
Oral liquid carnitine 50 mg/kg/day in 2 doses in combination with oral valproate capsules
in 2 to 3 doses to maintain overnight serum level trough 50 to 100 mg/dL or liquid
placebo twice daily in combination with placebo capsule 2 to 3 time a day. Duration of
treatment 12 months in active treatment and 6 months in placebo group. The placebo
group switched to active treatment after 6 months per protocol. Total follow-up 12
months
Outcomes
Change in functional score (MHFMS), change in quality of life (PedsQLT M ), change in
innervation via maximum ulnar compound muscle action potentials (CMAP), adverse
events. Change in muscle strength and change in pulmonary function was measured in
patient 5 years and older
Notes
Baseline differences in body mass index and gender between the different treatment
groups
MHFMS = Modified Hammersmith Functional Motor Scale; PedsQLT M = Pediatric
Quality of Life InventoryT M
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection Low risk
bias)
Randomly assigned
Allocation concealment (selection bias)
Low risk
Randomisation was performed using a permuted block design balancing for institution
Randomisation was performed central by
telephone
Blinding (performance bias and detection Low risk
bias)
All outcomes
Blinding of participants and key study personnel. Medical monitor was unblinded
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk
Not all outcome measures are available.
Missing data were not fully explained
Selective reporting (reporting bias)
Low risk
Adequate
Other bias
High risk
Cross over of placebo to treatment after 6
months
Drug treatment for spinal muscular atrophy types II and III (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
28
Tzeng 2000
Methods
Randomised (ratio 2:1), placebo-controlled, double-blind trial
Participants
9 patients who fulfilled international classification criteria for SMA type II or III and
have a homozygous deletion of the SMN1 gene
Interventions
Thyrotropin releasing hormone 0.1 mg/kg intravenous once a day or placebo. Duration
of treatment 29 days of treatment over a 34-day period, follow-up 35 days
Outcomes
Change in muscle strength (dynamometry), adverse events
Notes
Groups were not equal at baseline, with only women, only SMA II and older patients in
the placebo group. Muscle strength was measured bilaterally of deltoid, biceps, triceps,
wrist extension, hand grip, hip flexion, knee extension, and knee flexion
TRH = thyrotropin releasing hormone
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection Low risk
bias)
Randomly assigned (2:1)
Allocation concealment (selection bias)
Low risk
Patients were subsequently randomised by
double coin flip for each patient. Any
heads-tails combination was a participant; a
tails-tails combination was a control; and a
heads-heads combination was rejected and
the flip repeated. The randomisation was
done on a first arrival basis
Blinding (performance bias and detection Low risk
bias)
All outcomes
All investigators and participants were
blinded. Only the pharmacist was unblinded
Incomplete outcome data (attrition bias)
All outcomes
Low risk
Adequate
Selective reporting (reporting bias)
Low risk
Adequate
Other bias
High risk
Differences in baseline characteristics. Underpowered
Drug treatment for spinal muscular atrophy types II and III (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
29
Wong 2007
Methods
Randomised, placebo-controlled, double-blind trial
Participants
55 patients who fulfilled international classification criteria for SMA type II or III and
have a homozygous deletion of the SMN1 gene
Interventions
Creatine, age 2 to 5 years: 2 g once a day or placebo. Age 5 to 18 years: 5 gram once a
day or placebo. Duration of treatment 6 months, follow-up 9 months
Outcomes
2 to 5 years and 5 to 18 years: change in disability score (GMFM), change in quality
of life, adverse events. 5 to 18 years: change in muscle strength (QMT), change in
pulmonary function
Notes
Creatine group at baseline slightly weaker; follow-up inadequate (> 20% drop-out rate
and less than 9 months follow-up). Muscle strength was measured bilaterally for hand
grip, elbow flexion, knee extension, and knee flexion according to the Richmond Quantitative Measurement System
GMFM = gross motor function measure; QMT= quantitative muscle testing; PedQL
T M = Pediatric Quality of Life InventoryT M ; FVC = forced vital capacity
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection Low risk
bias)
Randomly assigned
Allocation concealment (selection bias)
Randomisation at central site. Method not
known
Unclear risk
Blinding (performance bias and detection Low risk
bias)
All outcomes
Patients, their families, investigators, evaluators, and study coordinators were blinded;
the study statistician was blinded to group
membership
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk
High drop-out rate is partially described
Selective reporting (reporting bias)
High risk
Raw data are not available, only graphs or
sum scores. Individual outcomes of patients
are not given, so extremes (high or low
scores) can not be evaluated
Other bias
High risk
Lack of power and high rate of drop-outs
(>20%)
Drug treatment for spinal muscular atrophy types II and III (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
30
Characteristics of excluded studies [ordered by study ID]
Study
Reason for exclusion
Abbara 2011
Non-randomised, open label. Study was to assess pharmacokinetics of riluzole in patients with SMA types II
and III
Brahe 2005
Not randomised, not controlled. Pilot trial. Study was on the effect of phenylbutyrate on human SMN expression
in blood
Brichta 2006
Not randomised, not controlled. Pilot trial. Study was on the effect of valproate on human SMN expression in
blood
Chang 2002
Not randomised, not controlled. Pilot trial. Study was on the effect of hydroxyurea on clinical manifestations
and human SMN expression in blood
Folkers 1995
Not randomised, not controlled. Observational study that included 1 patient with SMA type III/IV
Kato 2009
Case report
Kinali 2002
Not randomised, not controlled. Pilot trial
Liang 2008
Not controlled
Mercuri 2004
Not randomised, not controlled. Pilot trial
Merlini 2003
Not controlled (no placebo was given, compared treatment with no treatment, not blinded)
Nascimento 2009
Case series. Not controlled, not randomised
Pane 2008
Not randomised, not controlled. Pilot trial
Piepers 2010
Not controlled, not randomised. Case series
Swoboda 2009
Not controlled (no placebo was given). Open label trial
Tsai 2007
Not randomised, not controlled
Weihl 2006
Not randomised, not controlled. Retrospective study on patients with SMA types III and IV
Drug treatment for spinal muscular atrophy types II and III (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
31
Characteristics of studies awaiting assessment [ordered by study ID]
Merlini 2007
Methods
Randomised, placebo-controlled, double-blind trial
Participants
110 patients with SMA type II or III aged 4 years or older
Interventions
Acetyl-L-carnitine 50 mg/kg/day (maximum 3 g/day) (route not mentioned) or placebo. Duration of treatment 9
months, follow-up 12 months
Outcomes
Change in muscle strength arm end leg (myometry), change in functional score (time to walk 10 meters and to arise
from floor), change in pulmonary function (FVC), change in quality of life (SF-36 or CHAQ)
Notes
FVC = forced vital capacity; SF-36 = short form 36; CHAQ = Childhood Health Assesment Questionnaire
Characteristics of ongoing studies [ordered by study ID]
NCT00481013
Trial name or title
Valproic acid in ambulant adults with spinal muscular atrophy (VALIANT SMA)
Methods
Randomised, placebo-controlled, double-blind trial
Participants
Patients with SMA type II or III aged 18 years to 60 years
Interventions
Valproic acid (route and dose not mentioned) or placebo. Duration of treatment 6 months, follow-up 6
months
Outcomes
Change in muscle strength (MVICT; dynamometer), change in function (SMA-FRS), change in electrophysiology (motor unit number estimation and compound muscle action potential), SMN2 copy number,
change in pulmonary function (FVC and negative inspiratory force (NIF)), change in lean body mass (DEXA
scanning), change in distance walked in 6 minutes, change in time to climb four standard stairs, change in
quality of life (Modified-SIP)
Starting date
July 2007
Contact information
Sharon Chelnick, Ohio State University Medical Center, Department of Neurology, Columbus, Ohio, United
States, 43210
Notes
After 6 months all patients are placed on treatment
This study is ongoing, but not recruiting patients
MVCIT = maximum voluntary contraction in time; SMA-FRS = spinal muscular atrophy functional rating
scale; FVC = forced vital capacity; DEXA = Dual energy X-ray absorptiometry; Modified-SIP = ModifiedSickness Impact Profile
Drug treatment for spinal muscular atrophy types II and III (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
32
NCT00533221
Trial name or title
Pilot study of growth hormone to treat SMA types II and III
Methods
Randomised, placebo-controlled, double-blind, cross-over trial
Participants
Patients with SMA type II or III aged 6 years to 35 years
Interventions
Somatotropin (route and dose not mentioned) or placebo. Cross-over (duration of treatment not mentioned)
Outcomes
Change in strength (handheld myometry), functional (time) tests, lung function, quality of life, adverse events
Starting date
October 2008
Contact information
Rudolf Korinthenberg, University Medical Centre Freiburg, Children’s Hospital, Germany
Notes
This study is ongoing, but not recruiting patients
NCT00568802
Trial name or title
A pilot therapeutic trial using hydroxyurea in type II and type III spinal muscular atrophy patients
Methods
Randomised, placebo-controlled, double-blind trial
Participants
Patients with SMA type II and III aged 1 year to 10 years
Interventions
Hydroxyurea (dose and route) or placebo. Duration of treatment not mentioned
Outcomes
Motor function (GMFM and timed motor tests), adverse events, pulmonary function, motor unit number
estimation, SMN Protein and SMN mRNA
Starting date
January 2004
Contact information
Dr Ching H Wang, Stanford University School of Medicine, Stanford, California, United States, 94305
Notes
This study is ongoing, but not recruiting participants
GMFM = Gross Motor Function Measure; SMN protein = survival motor neuron protein
NCT00774423
Trial name or title
Study to evaluate the efficacy of riluzole in children and young adults with spinal muscular atrophy (SMA)
(ASIRI)
Methods
Randomised, placebo-controlled, double-blind trial
Participants
Patients with SMA type II or III aged from 6 years to 20 years
Interventions
Riluzole 50 mg/day orally or placebo. Duration of treatment 24 months, follow-up 24 months
Drug treatment for spinal muscular atrophy types II and III (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
33
NCT00774423
(Continued)
Outcomes
Motor function (MFM scale), FVC (spirometry), measure of functional independence (MFI), adverse events
and tolerance evaluation
Starting date
January 2006
Contact information
Brigitte Estournet, Hôpital Raymond Poincaré, Garches, France, 92380
Notes
This study is ongoing, but not recruiting participants
MFM = Motor Function Measure; FVC = forced vital capacity; MFI = measure of functional independence
NCT01302600
Trial name or title
Safety and efficacy of olesoxime in 3-25 year old SMA patients
Methods
Randomised, placebo-controlled, double-blind trial
Participants
Non-ambulatory patients with SMA type II or IIIa from 3 years to 25 years old
Interventions
Oral liquid olesoxime (TRO19622: cholest-4-en-3-one, oxime) 10 mg/kg once a day versus placebo
Outcomes
Change in functional scores (MHFMS and GMFM), change in electrophysiologic measures (CMAP and
MUNE), change in pulmonary function (FVC), change in quality of life (PedsQLT M ), adverse events
Starting date
Study initiation date: September 2010
Contact information
Enrico Bertini, MD Bambino Gesu’ Children’s Research Hospital, Unit of Molecular Medicine, Piazza S.
Onofrio 4, 00165 Rome, Italy
Notes
Study is ongoing and recruiting patients
MHFMS = Modified Hammersmith Functional Motor Scale; GMFM = Gross Motor Function Measure;
CMAP = compound muscle action potential; MUNE = motor unit number estimation; FVC = forced vital
capacity; PedsQLT M = Pediatric Quality of Life InventoryT M
Drug treatment for spinal muscular atrophy types II and III (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
34
DATA AND ANALYSES
This review has no analyses.
ADDITIONAL TABLES
Table 1. Diagnostic criteria for SMA types II and III
Age of onset between 6 and 18 months for SMA type II; age of onset after 18 months for SMA type III
Symmetrical muscle weakness of limb and trunk
Proximal muscles more affected than distal muscles and lower limbs more than upper limbs
No abnormality of sensory function
Serum creatine kinase (CK) activity not more than 10 times the upper limit of normal
Denervation on electrophysiological examination, and no nerve conduction velocities below 70% of the lower limit of normal. There
are no abnormal sensory nerve action potentials
Muscle biopsy showing atrophic fibers of both types, hypertrophic fibers of one type (usually type I), and in chronic cases type
grouping
No involvement of the other neurological systems, such as the central nervous system, hearing or vision
No involvement of non-neurological organ systems
Spinal surgery has not taken place
Genetic analysis to confirm the diagnosis, deletion or mutation of the SMN1 gene (5q11.2-13.3)
Table 2. Outcome of study Mercuri 2007
Phenylbutyrate
Placebo
Difference (95%CI)
P value
All ages
Number of participants 54
randomised
53
% of participants evalu- 83%
able for analysis
85%
Mean (SD) Hammer- 12.1 (9.60)
smith functional score
12.8 (9.86)
Drug treatment for spinal muscular atrophy types II and III (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
35
Table 2. Outcome of study Mercuri 2007
Mean (SD) change 0.60 (0.22)
in Hammersmith functional score
(Continued)
0.73 (0.29)
-0.13 (-0.84 to 0.58)
0.70
Mean (SD) change in 1.56 (6.94)
muscle strength arm (dynamometry)
-0.42 (8.61)
1.98 (-1.67 to 5.63)
0.74
Mean (SD) change mus- 4.26 (8.64)
cle strength leg (dynamometry)
3.22 (6.26)
1.04 (-2.46 to 4.54)
0.78
Mean (SD) change in 0.03 (0.17)
pulmonary
function (FVC % of predicted value in L)
-0.01 (0.27)
0.04 (-0.07 to 0.15)
0.39
Age > 5 years
RR (95% CI)
All ages
Number
events
of
adverse n.a.
n.a.
Number of participants 2
with adverse events
1
Number of severe ad- n.a.
verse events
n.a.
Number of partici- 1
pants with severe adverse
events
1
1.96 (0.18 - 21.0)
1.0
0.98 (0.06 - 15.3)
1.0
n.a. = not available
SD = standard deviation;
FVC = forced vital capacity; L = liter
Drug treatment for spinal muscular atrophy types II and III (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
36
Table 3. Outcome of study Miller 2001
Gabapentin
Total number of partici- 40
pants randomised
Placebo
Difference (95%CI)
P value
1 (-1 to 4)
0.30
0 (0 to 1)
0.26
4.0 (-2.3 to 10)
0.21
4.3 (-2.0 to 11)
0.18
44
Follow-up at least 9
months
Number (%) of partici- 37 (93%)
pants evaluable for analysis disability
34 (77%)
Median change in dis- 0
ability score (SMA-FRS)
-2
Number (%) of partici- 37 (93%)
pants evaluable for analysis quality of life
36 (82%)
Median change in qual- 0
ity of life (mini SIP)
0
Number (%) of partici- 36 (90%)
pants evaluable for analysis grip muscle strength
33 (75%)
Mean
-0.05 (9.16)
(SD) change in grip muscle strength (MVC)
-4.0 (16.2)
Number (%) of partici- 35 (88%)
pants evaluable for analysis arms muscle strength
32 (73%)
Mean (SD) change in 0.13 (9.77)
arms muscle strength
(MVC)
-4.2 (15.6)
Number (%) of partici- 33 (83%)
pants evaluable for analysis feet muscle strength
30 (68%)
Drug treatment for spinal muscular atrophy types II and III (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
37
(Continued)
Table 3. Outcome of study Miller 2001
Mean
1.6 (15.4)
(SD) change in feet muscle strength (MVC)
0.40 (16.5)
1.2 (-6.9 to 9.2)
0.77
Number (%) of partici- 31 (78%)
pants evaluable for analysis total muscle strength
29 (66%)
Mean (SD) change in 1.1 (18.1)
total muscle strength
(MVC)
-4.3 (24.5)
5.3 (-5.8 to 16)
0.34
Number (%) of par- 38 (95%)
ticipants evaluable for
analysis development of
walking
35 (80%)
Number of partici- 0
pants with development
of walking
0
-
-
Number (%) of partici- 36 (90%)
pants evaluable for analysis pulmonary function
34 (77%)
Mean (SD) change in -3.8 (6.22)
pulmonary
function (FVC % of predicted value in L)
-2.9 (6.05)
-0.86 (-3.8 to 2.1)
0.56
Number
events
adverse n.a.
n.a.
-
-
Number of participants n.a.
with adverse events
n.a.
-
-
Number of severe ad- n.a.
verse events
n.a.
-
-
Number of partici- n.a.
pants with severe adverse
events
n.a.
-
-
of
n.a. = not available
SD = standard deviation;
SMA-FRS = Spinal Muscular
Atrophy-FuncDrug treatment for spinal muscular atrophy types II and III (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
38
Table 3. Outcome of study Miller 2001
(Continued)
tional Rating scale; SIP =
Sickness Impact Profile;
MVC = maximum voluntary contraction; FVC
= forced vital capacity; L
= liter
Table 4. Outcome of study Tzeng 2000
TRH
Placebo
Difference (95%CI)
Number of participants ran- 6
domised
3
Number (%) of participants 6 (100%)
evaluable for analysis
3 (100%)
Mean (SD) change in muscle 0.82 (0.59)
strength (dynamometry)
0.48 (0.29)
0.34 (-0.54 to 1.22)
Number of adverse events
0
-
Number of participants with n.a.
adverse events
n.a.
-
Number of severe adverse 0
events
0
-
Number of participants with se- 0
vere adverse events
0
-
12
n.a. = not available
SD = standard deviation
Table 5. Outcome of study Wong 2007
Creatine
Placebo
Difference (95%CI)
P value
All ages
Number of participants 27
randomised
28
Drug treatment for spinal muscular atrophy types II and III (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
39
(Continued)
Table 5. Outcome of study Wong 2007
Number (%) of partici- 18 (67%)
pants evaluable for analysis disability
22 (79%)
Median change in dis- 0
ability score (GMFM)
-1
Number (%) of partici- 17 (63%)
pants evaluable for analysis quality of life
21 (75%)
Median change in qual- -5
ity of life (PedsQLT M ,
neuromuscular module)
2
1 (-1 to 2)
0.19
-5 (-11 to 3)
0.31
1.5 (-4 to 9)
0.18
2 (-8 to 13)
0.71
Age 2 to 5 years
Number of participants 8
randomised
12
Number (%) of partici- 7 (88%)
pants evaluable for analysis disability
10 (83%)
Median change in dis- 1
ability score (GMFM)
-2
Number (%) of partici- 6 (75%)
pants evaluable for analysis quality of life
9 (75%)
Median change in qual- 4.5
ity of life (PedsQLT M ,
neuromuscular module)
3
Age 5 to 18 yrs
Number of participants 19
randomised
16
Number (%) of partici- 11 (58%)
pants evaluable for analysis disability
12 (75%)
Drug treatment for spinal muscular atrophy types II and III (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
40
(Continued)
Table 5. Outcome of study Wong 2007
Median change in dis- -1
ability score (GMFM)
-0.5
Number (%) of partici- 11 (58%)
pants evaluable for analysis quality of life
12 (75%)
Median change in qual- -6
ity of life (PedsQL, neuromuscular module)
0
0 (-2 to 2)
0.77
-6 (-15 to 2)
0.11
Age 5 to 18 years
Number (%) of partici- 11 (58%)
pants evaluable for analysis muscle strength
11 (69%)
Mean (SD) change in -0.34 (6.98)
arms muscle strength
(QMT)
1.49 (8.50)
-1.83 (-8.75 to 5.09)
0.59
Mean
1.51 (4.21)
(SD) change in legs muscle strength (QMT)
0.93 (3.06)
0.58 (-2.70 to 3.85)
0.72
Mean (SD) change in 1.17 (9.67)
total muscle strength
(QMT)
2.42 (10.3)
-1.25 (-10.12 to 7.61)
0.77
Number (%) of partici- 11 (58%)
pants evaluable for analysis pulmonary function
12 (75%)
Mean (SD) change in -0.27 (14.5)
pulmonary
function (FVC % of predicted value in L)
-0.83 (11.5)
0.56 (-10.75 to 11.87)
0.92
RR (95% CI)
All ages
Number
events
of
adverse 55
43
1.28 (0.96 - 1.67)
Drug treatment for spinal muscular atrophy types II and III (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
0.06
41
(Continued)
Table 5. Outcome of study Wong 2007
Number of participants 13
with adverse events
16
0.84 (0.51 - 1.40)
0.59
Number of severe ad- n.a.
verse events
n.a.
-
-
Number of partici- n.a.
pants with severe adverse
events
1 (dead)
-
-
n.a. = not available
GMFM = Gross Motor
Function Measure; PedsQLT M = Pediatric Quality of Life InventoryT M ;
SD = standard deviation; QMT = quantitative muscle test; FVC =
forced vital capacity; L =
liter
Table 6. Outcome of study Swoboda 2010
Valproate and acetyl-L- Placebo
carnitine
Difference (95%CI)
P value
0.64 (-1.22 to 2.54)
0.50
0.12 (-0.33 to 0.57)
0.59
All ages
Number of participants 31
randomised
30
Number (%) of partici- 28 (90%)
pants evaluable for analysis disability (MHFSM)
28 (93%)
Mean
0.82 (2.88)
change (SD) in disability score (MHFSM) at 6
months
0.18 (3.98)
Number (%) of partici- 19 (61%)
pants evaluable for analysis of nerve innervation
value (CMAP)
19 (63%)
Mean (SD) change in to- 0.02 (0.70)
tal
amplitude
CMAP from baseline to
-0.10 (0.66)
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Table 6. Outcome of study Swoboda 2010
(Continued)
6 months
Number (%) of partici- 27 (87%)
pants evaluable for analysis of quality of life
(PedsQLT M ) from baseline to 12 months
27 (90%)
Mean (SD) change in -1.9 (13.6)
quality of life (PedsQL
T M ) from baseline to 12
months
0.3 (12.9)
-2.2 (-9.44 to 5.04)
0.54
0.24 (-3.28 to 3.76)
0.89
0.85 (-1.25 to 2.95)
0.42
Age < 3 years old
Number (%) of partici- 12 (52%)
pants evaluable for analysis disability (MHFSM)
11 (48%)
Mean
change 1.33 (2.27)
(SD) in disability score
(MHFSM) from baseline to 6 months
1.09 (5.37)
Age 3-8 years old
Number (%) of partici- 18 (47%)
pants evaluable for analysis disability (MHFSM)
17 (45%)
Mean
change 0.44 (3.29)
(SD) in disability score
(MHFSM) from baseline to 6 months
-0.41 (2.79)
Age 5 years and older
Number (%) of partici- 7
pants evaluable for analysis muscle strength in
arms (myometry)
7
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Table 6. Outcome of study Swoboda 2010
(Continued)
Mean (SD) change in 0.64 (0.6)
arms muscle strength
(myometry) from baseline to 6 months
0.07 (1.04)
0.57 (-0.42 to 1.56)
0.23*
Number (%) of partici- 6
pants evaluable for analysis muscle strength in
legs (myometry)
4
Mean (SD) change 0.55 (0.83)
in legs muscle strength
(myometry) from baseline to 6 months
-0.85 (2.22)
1.40 (-0.85 to 3.65)
0.19*
Number (%) of partici- 7
pants evaluable for analysis muscle strength in
both arms and legs (myometry)
8
Mean (SD) change in to- 1.18 (0.91)
tal muscle strength (myometry) from baseline to
6 months
-0.25 (2.47)
1.43 (-0.92 to 3.78)
0.21
Number (%) of partici- n.a.
pants evaluable for analysis pulmonary function
(FVC)
n.a.
n.a.*
n.a.*
Mean (SD) change n.a.
in pulmonary function
(FVC) from baseline to 6
months
n.a.
-
-
Number
of 23 (77)
adverse events (%) from
baseline to 6 months
18 (58)
RR= 1.32 (95% CI 0.92 to 1. 0.17
89)
Number of participants n.a.
with adverse events
n.a.
-
Number of severe ad- 6 (20)
verse events (%) from
2 (6)
RR= 3.1 (95% CI 0.68 to 14. 0.15
2)
All ages
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Table 6. Outcome of study Swoboda 2010
(Continued)
baseline to 6 months
Number of partici- n.a.
pants with severe adverse
events
n.a.
-
-
n.a. = not available
MHMFS = Modified
Hammersmith Functional Motor Scale; SD =
standard deviation; FVC
= forced vital capacity;
PedsQLT M = Pediatric
Quality of Life InventoryT M ; CMAP = compound maximum action
potential
*= underpowered
Table 7. Outcome of study Chen 2010
Hydroxyurea
Placebo
Difference (95%CI)
P value
-1.88 (-3,90 to 0.14)
0.07
-0.55 (-2.65 to 1.55)
0.60
All ages
Number of participants 37
randomised
20
Number (%) of partici- 37 (100)
pants evaluable for analysis disability (GMFM)
20 (100)
Mean change (SE) in dis- 0.14 (0.57)
ability score (GMFM)
2.02 (0.88)
Number (%) of par- 37 (100)
ticipants evaluable for
analysis muscle strength
(MMT)
20 (100)
Mean change (SE) in -0.58 (0.56)
muscle strength (MMT)
-0.03 (0.98)
Number (%) of partici- 37 (100)
pants evaluable for pulmonary function (FVC)
20 (100)
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Table 7. Outcome of study Chen 2010
Mean (SE) change in -0.21 (0.06)
pulmonary function
(Continued)
-0.22(0.12)
0.01 (-0.23 to 0.25)
0.93
Non-ambulatory
patients
Number (%) of partici- 26 (100)
pants evaluable for analysis disability (MHFMS)
12 (100)
Mean change (SE) in dis- 0.02 (0.03)
ability score (MHFMS)
0.04 (0.04)
- 0.02 (-0.13 to 0.09)
0.70
Number of adverse 224
events episodes
129
-
-
Mean number (SD) of 6.05 (3.43)
adverse events episodes
per participant
6.45 (2.91)
-0.4 (-2.21 to 1.41)
0.66
Number of participants n.a.
with at least ≥ 1 adverse
event
n.a.
Number of severe ad- 19
verse events episodes
10
-
-
Mean number (SD) 0.51 (1.04)
of severe adverse events
episodes per participant
0.50 (0.83)
0.01 (-0.77 to 0.79)
0.98
Number of participants n.a.
with at least ≥ 1 severe
adverse events
n.a.
-
-
Number of participants 2 (5)
(%) discontinued intervention
0 (0)
-
-
All ages
n.a. = not available
GMFM = Gross Motor Function Measure;
MMT = manual muscle
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Table 7. Outcome of study Chen 2010
(Continued)
testing; FVC = forced vital capacity; MHFMS =
Modified Hammersmith
Functional Motor Scale;
SD = standard deviation;
SE = standard error
APPENDICES
Appendix 1. MEDLINE OvidSP search strategy
Limits 1991-2011
1 randomized controlled trial.pt.
2 controlled clinical trial.pt.
3 randomized.ab.
4 placebo.ab.
5 drug therapy.fs.
6 randomly.ab.
7 trial.ab.
8 groups.ab.
9 or/1-8
10 exp animals/ not humans.sh.
11 9 not 10
12 exp Muscular Atrophy, Spinal/
13 (Werdnig adj Hoffman$).mp.
14 (Kugelberg adj Welander).mp.
15 (spinal adj5 muscul$ adj5 atroph$).mp.
16 MUSCULAR DISORDERS, ATROPHIC/
17 or/12-16
18 11 and 17
Appendix 2. EMBASE OvidSP search strategy
Limits: 1991-2011
1 crossover-procedure/
2 double-blind procedure/
3 randomized controlled trial/
4 single-blind procedure/
5 (random$ or factorial$ or crossover$ or cross over$ or cross-over$ or placebo$ or (doubl$ adj blind$) or (singl$ adj blind$) or assign$
or allocat$ or volunteer$).tw.
6 or/1-5
7 human/
8 6 and 7
9 nonhuman/ or human/
10 6 not 9
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11 8 or 10
12 spinal muscular atrophy/ or hereditary spinal muscular atrophy/
13 (Werdnig adj Hoffman$).mp.
14 (Kugelberg adj Welander).mp.
15 (spinal adj5 muscul$ adj5 atroph$).mp.
16 or/12-15
17 11 and 16
Appendix 3. CENTRAL search strategy
#1MeSH descriptor Muscular Atrophy, Spinal explode all trees
#2(Werdnig NEAR Hoffman*)
#3(Kugelberg NEAR Welander)
#4MeSH descriptor Muscular Disorders, Atrophic explode all trees
#5(#1 OR #2 OR #3 OR #4)
Appendix 4. ISI Web of Science search strategy
Limits :
1991-2011
Science Citation Index Expanded
Conference Proceedings Citation Index -Science (CPCI-S)
#1
TS=(random* trial) OR TS=(random* study) OR TS=(random* treatment) OR TS=(randomi* therap*)
#2
TS=(placebo) OR TS=(blind*) OR TS=(control*) OR TS=(crossover) OR TS=(cross-over)
#3
TS=(trial) OR TS=(study) OR TS=(treatment) OR TS=(treated) OR TS=(therap*)
#4
TS=(random*)
#5
#2 SAME #3
#6
#1 OR #5
#7
#4 AND #6
#8
TS=(spinal muscular atrophy) OR TS=(sma) OR TS=(hereditary spinal muscular atrophy) OR TS=(proximal spinal muscular
atrophy)
#9
TS=(Werdnig hofman*) OR TS=(werdnig)
#10
TS=(Kugelberg) OR TS=(Welander)
#11
TS=((cause* OR etiolog* OR origin) SAME (unknown OR without OR various OR variable OR different))
#12
#9 SAME #10
#13
#9 SAME #11
#14
#8 OR #12 OR #13
#15
TS=proximal OR TS=(juvenile OR intermediate OR infantile)
#16
TS=(spinal muscular atrophy OR sma)
#17
#15 SAME #16
#18
#14 OR #17
#19
#7 AND #18
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Appendix 5. Clinical Trials Registry of the U.S. National Institute of Health search strategy
1 spinal muscular atrophy
2 treatment
WHAT’S NEW
Last assessed as up-to-date: 8 March 2011.
Date
Event
Description
15 February 2012
New citation required but conclusions have not Change in listing of authors to include Dr WL van
changed
der Pol. This corrects an error in the authorship of this
update
15 February 2012
Amended
’Declaration of interest’ and ’Contributions of authors’
updated; no other changes to text
HISTORY
Protocol first published: Issue 4, 2006
Review first published: Issue 1, 2009
Date
Event
Description
31 March 2011
New citation required but conclusions have not changed RI Wadman included as new lead author.
8 March 2011
New search has been performed
Databases were searched and review was updated. Two
new trials were found
30 July 2008
Amended
Converted to new review format.
CONTRIBUTIONS OF AUTHORS
All authors contributed substantially to the concept and design of the review. Dr Bosboom and Dr Vrancken performed data extraction
and analyses for the original review. Dr Bosboom wrote the first draft of the original review and the other co-authors contributed to
subsequent revisions for important intellectual content. Drs Wadman, Vrancken and Van der Pol updated the review in 2011 and the
other authors approved the revisions.
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49
DECLARATIONS OF INTEREST
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 SMA 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 a contract with ISIS for a trial of 396443-CS1 in SMA patients. She also receives
funding for research from PTC Therapeutics and GSK for studies in Duchenne muscular dystrophy.
Drs Van den Berg, Vrancken, Van der Pol and Wadman are involved as investigators at a participating centre in the ongoing trial on
the safety and efficacy of cholest-4-en-3-one, oxime for children with SMA types II and IIIa (NCT01302600). They do not receive
any funding from the pharmaceutical industry.
Dr Bosboom has no conflict of interest.
Dr Wokke has no conflict of interest.
SOURCES OF SUPPORT
Internal sources
•
•
•
•
•
University Medical Center Utrecht, Department of Neurology and Neuromuscular diseases, Utrecht, Netherlands.
University Medical Center Utrecht, Department of Child Neurology, Utrecht, Netherlands.
Texas Scottish Rite Hospital for Children, Dallas, USA.
Cochrane Neuromuscular Disease Group, King’s College London School of Medicine, London, UK.
University Medical Center Utrecht, Department of Biostatics and Clinical Epidemiology, Utrecht, Netherlands.
External sources
• No sources of support supplied
DIFFERENCES BETWEEN PROTOCOL AND REVIEW
The ’Risk of bias’ methodology was revised in this update according to the Cochrane Handbook for Systematic Reviews of Interventions
(Higgins 2008).
The search strategy was adjusted. 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.
Change in forced vital capacity (FVC), as a percentage of FVC predicted for height, was added as a secondary outcome measure. 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.
INDEX TERMS
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Medical Subject Headings (MeSH)
Acetylcarnitine [therapeutic use]; Amines [therapeutic use]; Creatine [therapeutic use]; Cyclohexanecarboxylic Acids [therapeutic use];
Hydroxyurea [therapeutic use]; Neuroprotective Agents [∗ therapeutic use]; Phenylbutyrates [therapeutic use]; Randomized Controlled
Trials as Topic; Spinal Muscular Atrophies of Childhood [∗ drug therapy]; Thyrotropin-Releasing Hormone [therapeutic use]; Valproic
Acid [therapeutic use]; gamma-Aminobutyric Acid [therapeutic use]
MeSH check words
Adolescent; Child; Child, Preschool; Humans
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