Neuromuscular Disorders
Volume 15, Issue 11 , Pages 802-816, November 2005

134th ENMC International Workshop: Outcome Measures and Treatment of Spinal Muscular Atrophy11–13 February 2005Naarden, The Netherlands

Department of Laboratories, Unit of Molecular Medicine, Bambino Gesu' Childrens Research Hospital, P.za S. Onofrio, 4, 00165 Rome, Italy

Received 3 July 2005

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1. Introduction 

The 134th ENMC workshop on outcome measures and treatment of SMA attended the meeting in Naarden, The Netherlands, during the weekend of the 11–13th February 2005. It was attended by 30 active participants from Belgium, France, Germany, Italy, Poland, Spain, Switzerland, Turkey, The Netherlands, United Kingdom and USA, including three patient representatives.

The aim of the meeting was to put forward a concerted action to obtain consensus on the methods for following up patients with SMA, and measuring their motor disability.

Spinal muscular atrophy (SMA) is an autosomal recessive disorder that affects the spinal cord neurons, and is clinically characterized by muscle weakness and genetically by mutations in the Survival Motor Neuron (SMN) gene. Children with SMA experience weakness over a wide range of severity. Type 1 SMA are never able to sit independently and generally die in infancy. Type 2 SMA can sit but often develop severe pulmonary and orthopaedic complications, and SMA type 3 children acquire the ability to walk although this might be lost during the course of the disease. In all forms of SMA the most rapid rate of decline is early in the course of the disease, with a progressively slower rate of decline over time, and sometimes years are needed to appreciate any further deterioration [1]. Recent understanding of the pathogenesis of SMA has raised hopes that specific therapeutic approaches might be possible. There are normally two copies of SMN on each chromosome, the primary gene copy called SMN1, and almost an identical copy, SMN2. Loss of SMN1 is essential to the pathogenesis of SMA, while the severity of the disease is primarily related to the number of copies of SMN2. Approximately two copies of SMN2 (∼20% normal protein levels) very frequently produce SMA type 1, three copies are correlated mostly with SMA2, four copies with SMA3, while carriers for SMA (presumably ∼60% normal SMN protein abundance) are asymptomatic [2], [3], [4]. Thus, administration of agents capable of increasing the expression of SMN protein levels may improve outcome in SMA. Recent indications suggest that such agents exist, even among drugs already licensed for use. A concentrated effort to discover the best of the candidate agents is now proceeding, and these agents are being evaluated in well-characterized SMA mouse models and human cell lines, prior to human testing.

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2. Pathogenic mechanisms in SMA. Challenges for therapy 

In a brief introduction, Anita Macaulay from the UK Jennifer Trust on SMA, representing the SMA patient organisations emphasized the role of the SMA patient organisations in helping with the funding and recruitment of patients.

The first part of the meeting summarised the recent knowledge achieved on the pathogenesis and physiopathology of SMA. Arthur Burghes gave a broad introduction on the pathogenesis of SMA derived from his experience on animal models. Both SMN genes are ubiquitously expressed and encode very similar proteins, but differ in their splicing patterns: SMN1 produces only full-length transcripts, while SMN2 derived transcripts mainly lack exon 7. SMN protein lacking exon 7 does not oligomerize effectively, and appears to be unstable and rapidly degraded [5]. Mutations in SMN2, do not cause disease. The SMN protein is important for RNP complex assembly particularly of small nuclear ribonucleoprotein particle (snRNP), and heterogeneous nuclear ribonucleoprotein R (hn-RNP-R). Recent data show that hn-RNP-R co-localizes with SMN in distal axons of embryonic motor neurons [6]. SMN also has been shown to localize in the growth cones and branch points of developing neurons [7], [8], [9]. A homozygous knockout of the single murine Smn gene (Smn-/-mice) is lethal to the embryo. The introduction of the SMN2 gene into Smn-/-mice creates a viable animal model [10], [11]. Two copy SMN2Smn-/-mice exhibit a type I SMA phenotype and die by 8 days; 8–16 copies of SMN2 completely ameliorate the disease phenotype. Inducing SMN2 to produce higher levels of SMN protein therefore seems an attractive option in treating SMA. However, the time at which high levels of SMN from SMN2 are needed to prevent SMA is not clear.

A number of groups have reported molecules capable of inducing SMN2 to produce higher levels of SMN [12], [13], [14], [15].

In collaboration with Dr Beattie's group at Ohio State University, SMA has been modeled in zebrafish, a vertebrate model organism with well-characterized motor neuron development. Using antisense morpholinos to reduce Smn levels throughout the entire embryo, they found motor axon-specific pathfinding defects. Reducing Smn protein levels in the developing embryo resulted in motor axon specific truncations and branches, independent of motor neuron cell death. Moreover, by decreasing Smn levels in single motor neurons, they showed that these defects are due to a cell-autonomous function of Smn in motor neurons. These data reveal that one of the earliest consequences of Smn protein reduction is severely compromised motor axon outgrowth, indicating an essential role for Smn in motor neuron development [16]. In other transgenic mice expressing SMNDelta7 (Δ7) and crossed onto a severe SMA background, they found that Δ7 is not detrimental in that it extends survival of SMA mice from 5.2 to 13.3 days. SMN and Δ7 can associate with each other which suggest that this association stabilizes Δ7 protein turnover and ameliorates the SMA phenotype by increasing the amount of oligomeric SMN. When Δ7 and full-length SMN are expressed with a molar ratio of ∼1:1 they are able to interact, but if full-length SMN is less than 50%, it does not make proper complexes. The reported increased survival of the Δ7 SMA mice will facilitate testing of therapies and indicates the importance of considering co-complexes of SMN and Δ7 when analysing SMN function [17]. A number of high throughput screens for compounds capable of up regulating SMN2 expression have been performed. Among the compounds identified, some are toxic, others are known drugs. Particularly interesting are the HDAC (histone deacetylase) inhibitors. Some such as valproic acid (VPA) do alter the splicing of SMN2 but this is not true of all HDAC inhibitors. For instance, trichostatin A (TSA) does not increase full-length SMN. Most compounds to date have relatively high dose effects and most have short half-lives. We do not know what levels these compounds have to reach in motor neurons to give a therapeutic effect. Neuroprotective therapies increasing the expression of SMN seem promising as motor unit loss occurs late [11]. However, the requirement for high levels of SMN early in the development of the Zebrafish motor axon begs caution and in particular it is not clear when high levels of SMN are required to prevent the clinical manifestations of SMA.

Preliminary experiments by Matthew Butchbach (Neuroscience meeting abstract 2004) administered phenylbutyrate to mice and produced a significant increase in lifespan in most animals but not all. However, they did not see an increase in SMN with treatment in any tissues by Western blot [18].

Recent experiments applying gene therapy by a lentiviral vector expressing SMN and capable of retrograde axonal transport restored SMN to motor neurons, but had marginal effects on survival [19]. Distribution of lentivirus, and what target tissues are actually important as well as when to restore SMN seem critically important in improving gene therapy. Both when and where high levels of SMN are needed to prevent SMA also need to be better understood.

Brunhilde Wirth summarized the different splicing mechanisms between SMN1 and SMN2. SMN2 produces a very low amount of full-length SMN protein due to disruption of an exonic splicing enhancer (ESE) [20]. However, over expression of the splicing factor Htra2-beta1 that binds to an ESE localized in the middle part of exon 7 restores the correct splicing to almost 80%. Therefore, activation of the SMN2 transcription rate or modulation of its splicing pattern is likely to be clinically beneficial [21].

Her group showed that VPA, a short-chain fatty acid HDAC inhibitor, is able to increase the protein level of SMN2 by 2- to 4-fold through transcription activation and restoration of the correct splicing of SMN2 via increased levels of Htra2-beta1 in fibroblast cell lines from SMA patients [22]. Furthermore, VPA raises the SMN protein level also in neuronal tissue, such as cultured rat and human hippocampus brain slices. VPA is an FDA approved drug used for more than three decades in epilepsy treatment. Wirth's group carried out a first clinical trial in parents of SMA patients. Six of ten SMA parents had increased SMN2 levels of 40–300%. Her results were confirmed shortly later by another group [23].

Giving VPA to produce levels of 70–80μg/ml in serum in a few type I–III SMA patients showed potential benefit after 5–6 months of treatment mainly in the younger patients. However, some patients had decreased carnitine levels that had to be restored by oral l-carnitine administration. A systematic placebo-controlled multicentre clinical trial with VPA in type I SMA patients is in preparation in Germany (www.initiative-sma.de).

Francesco Tiziano from the group of Christina Brahe presented their data on the possibility to activate SMN2 gene expression by treatment with sodium 4-phenylbutyrate (PB), another inhibitor, has been used for several years for the treatment of the urea cycle disorders in young patients, including newborns, and is well tolerated. First, the effect of PB in SMA fibroblast cell cultures was studied. By using real-time PCR, PB treatment showed effectiveness in significantly increasing the levels of full-length SMN2 (SMN-fl) transcripts in most but not all cell lines. An increase was also found in SMN protein levels and in the number of Gems, nuclear structures in which the SMN protein is concentrated. No obvious correlation between the response to PB treatment and the number of SMN2 genes was observed [24]. To investigate whether the SMN2 gene expression could be further enhanced, several cell lines were treated simultaneously with PB and VPA. No further increase in response was observed in a PB high-responding cell line, whereas a slight to marked improvement in response was found in cell lines with low-responses to PB and VPA, showing that in at least some cultures the combined treatment can lead to a synergistic effect. Moreover, preliminary data obtained by treatment of muscle cell cultures showed an increase in SMN2 expression also in SMA myoblasts and myotubes.

To determine whether PB is also effective in enhancing SMN expression in vivo, a pilot trial was performed in which PB (triButyrate®) was administered orally to six SMA patients and three parents for 7 days. Leukocyte SMN-fl transcript levels were evaluated in blood samples taken before, during and after the treatment. Despite day-to-day variations in the relative amount of SMN mRNA, a statistically significant increase in SMN-fl transcripts was found during PB administration compared to baseline for the patients and parents [25]. These data provide the first evidence that SMN transcript levels can be enhanced in SMA patients by the administration of a drug and suggest that PB might be beneficial to SMA patients.

Judith Melki presented a review on her experiments pointing to neuroprotection and trying to develop stem cell approaches in SMA models as possible therapeutic strategies. Characterization of the neuronal SMA mouse model, in which homozygous deletion of Smn exon 7 has been directed to neurons, has suggested that loss of motor neuron cell bodies is a late manifestation and results from a dying back process in SMA [26]. Riluzole is thought to exert a membrane-stabilizing effect limiting glutamate release, which is involved in excitotoxic mechanism [27]. In addition, riluzole exhibits neurotrophic activity [28]. These data led the group of Melki to determine whether the neuroprotective activity of riluzole has any beneficial effect on SMA disease progression. Treatment of neuronal mutant mice with riluzole started from 21 days of age and was able to improve median survival (15% increase) and to exert a protective effect against aberrant cytoskeletal organization of motor synaptic terminals but not against loss of proximal axons [29]. To investigate further whether neuroprotection might represent a valuable therapeutic approach in SMA, systemic delivery of cardiotrophin-1 (CT-1), a neurotrophic factor belonging to the IL-6 cytokine family, was performed. Intra-muscular injection of adenoviral vector expressing CT-1 to neonates, even at very low dose, improved median survival by 32%, delayed motor defect of mutant mice and reduced loss of proximal motor axons and aberrant cytoskeletal organization of motor synaptic terminals by15%. In spite of severity of the SMA phenotype, CT-1 slowed down disease progression [30]. These two approaches provided the first evidence that progression of the neuronal phenotype of SMA can be attenuated. Molecules having neuroprotective effects such as riluzole may thus be regarded as candidates for therapeutic trials in human SMA.

To evaluate the therapeutic benefit of adult stem cells in a muscle model of SMA, in which homozygous deletion of Smn exon 7 has been directed to muscle, bone marrow (BM) transplantation was performed. This model is characterized by a severe myopathy, progressive motor paralysis and loss of muscle fibres [31]. After low dose irradiation (6Gy), transplantation of wild type BM cells improved motor capacity (+85%) which correlated with a normalization of myofiber number associated with a higher proportion of regenerating myofibers (+56%), CD34 and Pax7 satellite cells (+52 and +41%, respectively). The remarkable attenuation of mutant phenotype contrasted with a low recruitment of BM-derived cells (BMDC) into myofibers (∼2%). A higher proportion of regenerating myofibers was observed in the vicinity of BM-derived myofibers when compared to distant areas. Moreover, transplantation of mutant BM cells which provide deleted Smn alleles in myofibers only abolished these effects. These results strongly suggest that myofibers fused to or differentiated from wild type but not mutant BMDC deliver paracrine factor(s), which activate(s) skeletal muscle regeneration in vivo leading to therapeutic benefits (Salah et al., submitted).

The drawback of autopsy studies is that they demonstrate the end-stage. SMA needs to be studied during the pre-symptomatic period in human development in order to gain insight into the mechanism of the disease.

Eduardo Tizzano presented preliminary results on pre-symptomatic studies performed in affected SMA fetuses, obtained from therapeutic abortions. A significant increase in DNA fragmentation was observed in the spinal cord of fetuses predicted to have type I SMA particularly around 12–15 weeks, a period that coincides with the establishment of functional neuromuscular synapses [32], [33]. This finding suggests a supraphysiologic cell death as a possible disease mechanism during development. Furthermore, a down-regulation of Bcl-2 was detected in SMA motor neurons together with a delayed and irregular expression of Bcl-X. The pattern of expression of these anti-apoptotic proteins may account for the aberrant neuronal death described during the development of SMA fetuses [34].

The typical neurodegeneration changes described in motor neurons from autopsy material were not observed in these prenatal samples. This raised the question of whether motor neurons were more sensitive to cell death or whether they were already dysfunctional in the fetal period. Hence, the expression of choline acetyl transferase (ChAT) was investigated, as the most specific marker for cholinergic neurons. SMA spinal cords showed reduced ChAT expression with respect to controls. The proportion of motor neurons negative for ChAT immunostaining was similar in both groups suggesting that the surviving motor neurons in SMA fetuses could have a cholinergic function akin to that of controls. On the other hand, the chromatolytic motor neurons detected in SMA after birth were ChAT negative. Therefore, ChAT does not identify early pathogenic events in fetal SMA spinal cord. ChAT is rather a late marker for motor neuron degeneration and not a primary contributing factor [35].

Finally, SMN expression was studied in these samples. A high level of full-length (FL) SMN transcripts with tiny amounts of Δ7 isoform (of SMN1 origin) was detected in control fetal spinal cord, whereas SMA spinal cord showed a decrease in FL transcripts but a substantial increase in Δ7 (of SMN2 origin). Furthermore, there may not be a correspondence of SMN2 levels in different tissues. Clinically unaffected tissues, such as intestine, lung, adrenal gland, kidney and eye, compensate for the absence of SMN1, whereas in SMA motor neurons, the increase in Δ7 expression could contribute to the disease [36].

Thus, SMA may be considered a developmental disorder and that early intervention to prevent or delay motor neuron degeneration may be possible. The identification of pre-symptomatic SMA by newborn screening warrants further investigation and debate.

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3. Experience from completed trials as lessons for trials in SMA 

A natural history study of SMA was completed in 1994 by the Dallas-Cincinnati-Newington (DCN) group [37]. Results from the DCN study were used to design later trials conducted by AmSMART and Susan Iannaccone presented the trial using riluzole in SMA type I [38] (Box 1) and gabapentin in SMA type III [39] (Box 2). Bertini summarized the multicentre Italian randomized, controlled, open label trial of gabapentin in SMA type II and III patients (Box 3). Eugenio Mercuri presented his preliminary experience of phenylbutyrate in childhood SMA II and non-ambulant SMA III [41] (Box 4).

Box 1..
The US riluzole placebo controlled, randomized trial in SMA type 1 [38]

In the riluzole placebo controlled, randomized trial inclusion criteria were type I patients with homozygous deletions of SMN 1. Randomisation was in favour of drug 2:1. Primary outcome was mortality. Dose was based on surface area at 107mg/m2 and drug was added to cereal or formula milk. Ten patients were enrolled; seven received riluzole. There were three survivors. Age at diagnosis in the treated group was 2–10 months (mean 5.2); in the placebo group, 0.5–2 months (1.2). Age at death for the treated group was 5–22 months, mean 12.7, while for the placebo group age at death was 6–13 months, mean 9. The drug seemed to be safe and results justified a larger trial. No conclusion could be made regarding a possible benefit of riluzole because the treated and placebo groups might actually have been different, and because the later age of onset in the treated group suggested that the treated group possibly had a milder disease than the placebo group.

Box 2..
The US randomized, placebo controlled, double blind trial of gabapentin in adults with SMA [39]

In the US randomized, placebo controlled, double blind trial of gabapentin in adults with SMA the dose was 3600mg tid. The study was powered such that there was a 90% power to find a 30% increase in strength. Eighty-four patients were enrolled; 65 patients completed. Subjects with type II or III and over age 21 years were enrolled at eight sites across the United States. Inclusion criteria were genetic diagnostic confirmation, ability to sit alone, FVC>35%; age at onset was not considered. The primary outcome measure was a quantitative muscle test in four muscle groups (elbow flexion and hand grip bilaterally). Upper limbs were exclusively measured to avoid errors due to very low power in legs. Secondary efficacy variables included: FVC, SMA functional rating scale (SMAFRS, modified from ALS scale), and mini-Sickness Impact Profile (SIP). Drug efficacy was examined by comparing the percent change in strength for patients on drug versus placebo (intention-to-treat analysis). There was no difference between the placebo and drug groups in any outcome measure after 12 months of treatment.

Box 3..
The multicentre Italian randomized, controlled, open label trial of gabapentin [40]

The trial used gabapentin (up to 1800/mg bd) versus no treatment (Italian SMART) in 120 patients (age range 5–60 years) with type II or III spinal muscular atrophy for 12 months. This trial started when US trial almost finished. The power was 85% for detecting an increase of 35% in arm mega score of lower limbs. The maximum voluntary isometric contraction measured with a handheld myometer was the primary outcome measure, calculating the megascore (summing elbow flexion, hand grip, and three-point-pinch scores), and a leg megascore (summing knee flexion, knee extension, and foot extension scores). Forced vital capacity and timed tasks were also evaluated. Arm megascore improved by at least 30% in 24.6% of treated and 16.9% of untreated patients. The leg megascore improved by at least 30% in 37.7% of treated and 20.3% of untreated patients. The conclusion was that gabapentin produced a significant improvement in leg megascore at 6 months, which was more evident at 12 months, with a trend for improvement in arm megascore at 12 months. The treatment had no effect on forced vital capacity or timed functional tests and feeling of the patients was that they had no functional improvement in daily life. However, the trial was very useful to train many centres in Italy committed to SMA. One conclusion was that hand-held myometer measurements of foot dorsiflexors should be avoided (low reliability) while reliable strength measurements in the lower limbs can be obtained studying the knee extensors and knee flexors.

In a further analysis of these data [55] the investigators tried to analyse the relationship between motor function and muscle strength in the same 120 patients with spinal muscular atrophy (SMA). They measured muscle strength in the arms and legs by a hand-held dynamometer, forced vital capacity by a spirometer, and the time needed to walk 10m, arise from the floor, and climb steps. SMA patients had markedly reduced muscle strength, approximating 20% of that predicted from age- and gender-matched normative data. This severe muscle strength loss should be considered when setting endpoints in any future clinical trial of SMA. Knee extensors were the weakest muscles in SMA patients, and were much weaker than knee flexors. Muscle strength of the knee extensors correlated strongly with the timed tests of walking (P<0.001), climbing (P<0.001), and rising (P<0.001). The young ambulant SMA patients performed better than adults in all the timed tests and had greater muscle strength on knee extension. In addition, pulmonary function tests showed that FVC was related to motor function: ambulant patients had normal or mildly reduced FVC, whereas non-ambulant patients had, in general, a marked reduction. The study showed a good relationship between motor ability and muscle strength in SMA and suggested that age-related loss of function in SMA is likely due to loss of muscle strength.

Box 4..
Pilot open study of phenylbutyrate in childhood SMA II

This pilot trial using phenylbutyrate in childhood SMA II and non-ambulant SMA III evaluated tolerability and efficacy of phenylbutyrate (PB) in patients with spinal muscular atrophy (SMA). Ten out of 13 patient completed the study. One developed skin rash, and 2/3 would not take it because of bad smell and taste. Patients were confirmed by DNA studies (age range 2.6–12.7 years, mean age 6.01), and were started on oral PB (triButyrate) in powder or tablets. Children that had 5 to 12 years also were measured with hand held myometry and FVC.

The dosage was 500mg/kg per day (maximum dose 19g/d), divided in five doses (every 4h, skipping one night-dose) using an intermittent schedule (7 days on and 7 days off). Measures of efficacy were the change in motor function from baseline to 3 and 9 weeks, on the Hammersmith functional motor scale (HAMA) [42]. In children older than 5 years, muscle strength, assessed by myometry, and forced vital capacity were also measured. A significant increase in the scores of the HAMA between the baseline and both 3-weeks (P<0.012) and 9-weeks assessments (P<0.004) was found. Results indicated that PB might be beneficial to SMA patients without producing any major side effect. A larger prospective randomised, double-blind, placebo controlled trial is in progress.

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4. Natural history, standard care, and outcome measures 

Preliminary data obtained from the longitudinal application of reliable measurements on functional scores and strength in SMA patients have already shown important background information for comparing the outcome in future trials using therapeutic interventions [42], [43]. Klaus Zerres made a general introduction on his personal experience and what is known on the natural history of SMA (Box 5).

Box 5..
Data on natural history

The clinical picture is a continuum and any classification is artificial. The data even within patients belonging to one type show that progression and life expectancy strongly correlate with the age of onset [56]. The earlier the onset is, the more severe is the course and the more reduced is the life expectancy. On the basis of the analysis of data of 197 patients with SMA type I, who were not able to sit, survival probabilities at 2, 4, 10, and 20 years of age were 32, 18, 8 and 0% [46]. The survival rate among 240 type II patients (who sat but never walked) was 98.5% at 5 years and 68.5% at 25 years. SMA III (n=329) (those who walked and had symptoms before age 30 years) was subdivided into those with an onset before and after age 3 years (type IIIa, n=195; SMA IIIb, n=134). In patients with SMA III, life expectancy is not significantly less than the normal population. The probability of being able to walk at 10 years after onset was 70.3%, and at 40 years, 22.0% in SMA IIIa. For SMA IIIb, 96.7% were walking 10 years after onset and 58.7% at 40 years. The subdivision of type III SMA was justified by the probability of being ambulatory depending on age at onset; the prognosis differed for those with onset before or after age 3 years [57].

In 175 patients with SMA II, 73% of the patients sat within the normal age range (up to 9 months), the remainder learned to do so at ages between 10 and 30 months. In 266 SMA III patients, the walking milestone was passed with delay (given an upper normal limit of 18 months) in 10% of all and 16% of SMA IIIa patients (median age 13 months, range 9–53 months). There was a correlation between late sitting and walking in SMA III, since those who sat after 9 months were responsible for the majority of delayed walkers. The median age when becoming chairbound did not differ between early-onset SMA III patients who walked with delay and those who walked within the normal age range (10.2 versus 10.5 years). A significant proportion of patients with early-onset SMA classified as SMA II on the basis of achieved motor function turned out to be SMA III at later follow-up. It is important to reassess a child in the first 2–4 years, to determine whether walking can be achieved with or without aids, as children who start to walk late have a similar favourable outcome for ambulation compared to earlier walkers [58].

Russman et al. [37] showed that 50% of 159 SMA patients who could walk without assistance and whose onset was prior to age 2 years lost the ability to walk independently by age 12. Fifty percent of SMA patients who walked and whose onset was between 2 and 6 years of age lost walking ability by age 44 years. Fifty percent of SMA patients who could walk with assistance as their best function ever achieved, lost this ability by age 7 years, unrelated to age of onset; none could walk with assistance after age 14 years. Seventy-five percent of SMA patients who developed the ability to sit independently as their best function were still sitting after age 7 years independent of age of onset; 50% of this group could sit independently after age 14 years. Eighty-five percent of SMA patients who could walk could not negotiate stairs without holding onto a rail. They could raise their hands above the head; but, as they lost walking ability, they lost this function as well. Only one SMA patient whose maximum function was sitting independently could get to the sitting position on his own. Only two of these patients could hold their hands above their heads. All patients with SMA lose function over time. This loss occurs slowly and is related primarily to maximum function achieved; knowledge of age of onset provides helpful information, especially for predicting the loss of independent walking.

The clinical course and age of onset in siblings is similar within most affected sib ships belonging to the same type. Most of the discordant sib pairs belong to adjacent groups and those with a completely different course (type I versus III) are an exception. While the age of onset in affected individuals is comparable, the age of death can be extremely different especially in SMA type II and III, and cannot be regarded as a useful parameter for example in clinical trials. Since, there is a sex influence in the clinical course in SMA with a milder clinical course in females in certain age groups, gender has to be taken into account in any clinical trial.

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5. Breakout sections 

5.1. SMA type I 

The group related to SMA type I was lead by Eugenio Mercuri and Richard Finkel who defined inclusion and exclusion criteria for clinical trials in SMA-1. SMA-1 patients should be clinically as homogeneous as possible within a trial or separate cohorts should be used for analysis of differing subtypes. The clinical phenotype of type 1 can be subdivided into three fairly discrete groups that have distinctly different natural histories. Type 1a, the severe neonatal variant with joint contractures and a paucity of movement present at birth has a poor prognosis, often needing ventilatory support as a neonate. Type 1b is the typical SMA-1 patient having poor head control and difficulty handling oral secretions upon or shortly after presentation and has an intermediate prognosis. Type 1c is the minority of type 1 patients who achieve head control or who can sit with support and have the best prognosis. All patients must be genetically confirmed by a homozygous SMN deletion/point mutation, and by SMN 2 copy number.

As a basis for a multicentre clinical trial, there needs to be a consensus on routine management such that all patients in the placebo and treatment arms are given similar care. It is not yet possible to accomplish a wide consensus on standard care for SMA-1 because data were lacking but this is being pursued by the American and International task force lead by Chin H. Wang (Stanford University for the US group). It is crucial to clarify the management of respiratory complications. Non-invasive ventilation, particularly the use of Bilevel Positive Airway Pressure (BiPaP) and Continuous Positive Airway Pressure (CPAP) have led to increase life expectancy in SMA type I and have changed the natural history [44], [45], [46]. Moreover, Finkel suggested the need to assess growth and nutritional measurements, so that SMA-1 patients in a trial are not malnourished. This will in theory minimize falsely attributing clinical complications that are due to progression of disease or laboratory abnormalities to an adverse drug effect. Finkel's current longitudinal study of SMA-1 infants includes anthropometric assessment of growth measures (weight, length, head, chest and arm circumference), nutritional assessment (skinfold thickness, DEXA-derived estimates of lean body, bone and fat mass), and laboratory investigations (blood count, metabolic screen and other nutritional markers).

The primary outcome measure in a SMA-1 trial should be life expectancy (age at death). Several secondary outcome measures are in the process of validation in pilot studies, similar in scope to the SMA-2 studies [47]. Electrophysiological testing includes the motor unit number estimation (MUNE) in the ulnar nerve innervated muscles and maximal compound muscle action potentials (CMAPs) of the ulnar, phrenic, musculocutaneous and peroneal nerves [48]. Functional motor scales such as Test of Infant Motor Performance (TIMP—includes elicited measures and observed measures), Children's Hospital of Philadelphia SMA-1-Test of Strength (CHOP TOSS—includes an elicited motor scale, and a breathing pattern score) are being compared and appear to offer advantages over previously used instruments such as the Alberta Infant Motor Scale.

Bernd Reitter presented a scale for testing motor ability in SMA-1. This scale is based on the observation of spontaneous movements. The test has a high inter-rater reliability but needs a high degree of training and standardisation.

Respiratory measures are important to develop and validate for SMA-1, because progressive pulmonary disease is the main cause of death. Finkel's pilot study uses two testing systems. Respiratory inductive plethysmography involves using an elastic band over the chest and the abdomen and generates data at rest and when crying (maximal elicited effort) in terms of the phase angle and laboured breathing index. This appears to be a sensitive and safe measure of quantifying the degree of the paradoxical breathing pattern. A face-mask with pneumotach can reliably measure resting and crying breathing values that estimates the flow volume and pressure at the mouth (the inspiratory time, Ti, and total time of a tidal breath, Ttot), the maximum inspiratory pressure (MIP) generated against a brief occlusion at the mouth) and the related P100 (pressure at 100ms inspiration). The tension time of the respiratory muscles (Ttmus) can then be calculated, summating diaphragmatic and chest wall work. This is compared to the tension time index (TTi), from catheter-derived pressure measurements in the esophagus and stomach, which reflects isolated diaphragm pressure. The goal is to measure a FVC-like estimate in infants and a more encompassing measure of how much of the potential maximal work of breathing is used for tidal breathing.

For a quality of life measure, the PEDsQOL has been validated in several languages and a neuromuscular module is now being validated in SMA [49]. A measure of care given burden has not been used yet in families with SMA I children.

Richard Finkel presented then summarized the group's consensus of an ideal study design for a placebo-controlled, randomised, double blind clinical trial in SMA type I.

The goals for such a clinical trial network include conducting short-term trials of sufficient power to demonstrate whether or not a study drug is effective and to do so using safe, validated, responsive and inexpensive test instruments. Such studies would need to be multicentre and possibly multinational if recruitment of subjects were to be done within a short time frame. Ideally, multiple studies could be coordinated at different sites, utilizing common outcome measures so that the studies are comparable and meta-analysis would be meaningful. Drugs to be tested would have a biological basis within what is known about the molecular and physiological aspects of SMA. It is anticipated that combination therapy with different but complementary biological targets will ultimately be needed. The clinical trial design will benefit greatly from the application of a consistent baseline standard of care in both the placebo and intervention arm and uniformly at all sites. As local standards of care currently vary significantly, further discussion of ethical and health care funding issues will necessarily follow. Support of local SMA community and funding agencies will be critical to the success of these trial networks.

More details on the consensus of this group are summarized in Table 1, Table 2.

Table 1. Clinical trial design in SMA type I
Inclusion criteria:
1.SMA-1 phenotype excluding the neonatal onset form
2.All patients must be genetically confirmed by a homozygous SMN deletion/point mutation, and characterized by SMN 2 copy number. Those with a SMN2 copy number of 3 are predicted to have a milder form of type 1 and could be considered as a separate cohort
3.Enrolment into the trial within 3 months of first physician contact and 6 weeks of genetic confirmation
4.Ability of caregivers to follow the study protocol and come to study visits
Exclusion criteria:
1.Patients with the neonatal form of SMA (type 1a)
2.Presence of other significant medical conditions
3.Not participating currently (or previously) in another treatment or intervention trial
4.Not taking medication or supplements that have been shown in other trials to have even marginal benefit in SMA
5.Severe malnutrition? There are no data to support the conjecture that malnourished infants do fare less well than those who are suitably nourished. The use of anthropometric and nutritional assessments (as above) may help answer this question
6.Exclude those infants who have needed a certain level of ventilation for a defined duration, e.g. BiPAP for more than 16h a day for 2 or 4 weeks
Study design:
1.An adequately powered placebo controlled study. There are insufficient natural history data to use as the representative non-treatment group and the natural history is changing due to evolving standards of care. Whether a 2:1 drug: placebo randomisation can be used without having to increase the overall enrolment in the study will need further scrutiny when specific studies are designed
2.The primary outcome measure is longevity (time to death). Subjects who evolve to the point of needing chronic non-invasive ventilatory support for more than 16h a day for 2–4 weeks are not likely to wean to a lesser degree of such support and without which they would die. Such a parameter, if sufficiently conservative, could serve as an exit point from the study, i.e. serve as a proxy for death
3.Secondary outcome measures should include:a. A motor function scale. These are in the development process (Finkel, Ritter; above)b. Respiratory function measures that are reflective of the contribution of both the diaphragm and chest wall muscles towards the work of breathing and should be responsive to change over time (in the development phase—Finkel)c. Electrophysiological measures such as the MUNE and ulnar CMAPd. Quality of life and caregiver burden measures such as the PedsQL and the related neuromuscular module (AmSMART group)e. Biomarkers (At present neither SMN2 RNA or protein measurements from white cells or fibroblasts appear to reflect the disease process, Wirth)f. DEXA scan analysis of lean body mass, especially of limb segments are used. (at present not validated in SMA-1)
4Duration not more than 12 months, if longevity or equivalent is used as the primary outcome measure
5.Safety measures:a. Monitor for adverse drug effect with close attention to growth measures and laboratory blood testing (CBC, hepatic, renal and routine labs)b. Data safety monitoring committee that is independent of the study investigators, including an interim futility analysisc. Inclusion of an ethicist and members of the SMA support group community on advisory panelsd. Discourage or prohibit enrolment of patients if travel to the study site or other factors poses a greater risk than is the potential benefit from the study
Table 2. Drug trials currently in progress or planned for SMA-1
•Riluzole—AmSMART, S Iannaccone, PI. 11 sites, 44 subjects, open-label, 6 months treatment at 107mg/kg per day divided bid
•Hydroxyurea—Stanford, C Wang, PI. single site pilot trial, placebo controlled
•Phenylbutyrate—Project Cure, K Swoboda, PI. Single site
•Valproate—Germany, B Wirth, PI. Pilot, open-label study and randomized trial to start shortly, T Voit, PI.

5.2. SMA type II 

This group led by Susan Iannaccone and Francesco Muntoni considered inclusion and exclusion criteria. SMA type II includes patients who are able to sit independently for 30s or more when placed. The age group of patients that would be best for a trial would be between age 3 and 10 years, to reduce confounding factors such as poor compliance, contractures, and progressive lung disease. A SMN deletion/point mutation must be confirmed in all patients, as well as the SMN2 copy number. Stratification by age and weight should be considered because the outcome measures differ with age. Exclusion criteria would be more than 16h/day on mechanical ventilation either with BiPAP or tracheostomy; spinal fusion; severely progressive scoliosis (30° per years or curve>90°); and other pathology or medication.

A basic standard of care should be a requirement for inclusion and following experience with other neuromuscular disorders [50], [51], [52]. Specific parameters to monitor and actions to take regarding feeding, management of acute infections; management of frequent recurrent respiratory chest infections; prevention of pulmonary morbidity and respiratory failure have been proposed [52]. The principal key components leading to respiratory compromise are (see also Box 6): respiratory muscle weakness; bulbar dysfunction; weak cough; gastroesophageal reflux; and scoliosis.

Box 6..
Principal key components leading to respiratory failure in SMA

(a) Respiratory muscle weakness: SMA children with respiratory weakness show the characteristic pattern of involvement in SMA, intercostal muscle weakness with relative sparing of the diaphragm. Data so far indicate that the best and easiest parameter to monitor respiratory muscle strength in cooperative children with SMA is forced vital capacity (FVC), which is best expressed as percentage predicted for height. As children with SMA have normal intelligence, the FVC can often be obtained from 6 years or earlier.

The FVC values may be normal or near normal in stronger ambulant type III patients. Though the FVC is generally considered to remain stable over long period of time, Samaha et al [59] showed in 77 patients with type II and III that the height adjusted FVC did not increase with age in 35% of cases. In the 40 patients followed up serially, 57% lost height adjusted FVC and the absolute FVC decreased in 43% cases. Respiratory complications in SMA consist of a pattern of recurrent chest infections, often with lobar collapses, and this is more frequent in the early childhood years (2–6 years). In the age group 2–6 years, when respiratory infections are quite common, the children are not able to cooperate with formal testing (FVC) and one has to rely on clinical parameters for respiratory assessment. These include eliciting a history for frequent chest infection; symptoms of gastroesophageal reflux (GOR) and dysphagia; chest shape and pattern of breathing movements; respiratory rate and use of accessory muscles. These can be supplemented with pulse oximetry, chest X-ray and formal blood gas testing should there be a clinical indication. In the adolescent age group with SMA type II it is more frequent to assist to decreased FVC and nocturnal hypoventilation, leading to overt respiratory failure. Nocturnal hypoventilation can be suspected by history of symptoms of morning drowsiness, headaches, nausea, failure to thrive and confirmed by nocturnal sleep studies. A basic sleep study may consist of overnight oxymetry, which is available to all general paediatricians and can be performed on a domiciliary basis. For a complete evaluation of abnormal findings on the screening study, a detailed multichannel monitoring of overnight PO2, pCO2, rib cage movement, nasal air flow and sleep staging may be required at a specialist centres.

(b) Bulbar dysfunction: This is universal in infants with SMA I and results in feeding and swallowing difficulties and aspiration pneumonia, which often is the cause of death. The severity of bulbar dysfunction in SMA II is variable, and not necessarily correlated with the motor function. Bulbar dysfunction may result in silent or overt aspiration and may impair cough. The precise contribution of bulbar dysfunction to the development of respiratory complications is not entirely clear but from clinical experience it plays a significant role at least in a proportion of cases. Swallowing bulbar function can be evaluated by inquiry into symptoms of length of meal times; coughing/chocking during feeding; the need for diet modification and videofluoroscopy.

(c) Weak cough: This can be a sequela of low FVC, poor glottic closure and weakness of the expiratory and abdominal muscles. Cough impairment leads to atelectasis/lobar collapse.

(d) Gastroesophageal reflux (GOR): This is an under-recognised finding, which may contribute significantly to silent aspiration. Waterbrash and regurgitation at the back of the throat on lying down and in the mornings is one of the symptoms in these patients. GOR is best studied with a nasogastric probe pH monitoring studies.

(e) Scoliosis: The development of progressive scoliosis further impairs pulmonary mechanics, reduces respiratory reserve and affects the posture at meal times.

The group also made recommendations on pulmonary management (Box 7) and agreed to discuss optimal follow-up of respiratory care in an ENMC electronic forum after the Workshop.

Box 7..
Recommendation on pulmonary management in SMA II patients

It is recommended that forced vital capacity (FVC in % predicted) in the sitting position should be performed annually. When FVC is abnormal (>80%) an additional measurement in the supine position should be performed to detect potential diaphragm weakness (indicated by>20% drop from baseline). FVC<40% and/or diaphragm weakness constitute a significant risk of nocturnal hypoventilation. With FVC>60% there is a low risk of nocturnal hypoventilation. Continuous recording of overnight pulse oximetry (and end-tidal or transcutaneous CO2 if available) during sleep should be performed annually when FVC is<60% and more often when FVC is<40%. In patients less than 5-years-old in whom FVC cannot be measured, nocturnal pulse oximetry (and end-tidal or transcutaneous CO2 if available) should be performed at least annually. If continuous recording of overnight pulse oximetry is not available, the patient should not be left unassessed, but referred to a specialist centre. Moreover, PCF (peak cough flows) should be measured annually during a steady state and at any episode of chest infection to determine whether assisted coughing techniques and chest physiotherapy are indicated.

Future trials should be randomized and placebo controlled with a duration of at least 6 months. The recruitment of young children, that might be helpful in case a drug effect is best visible in children closer to the onset of the disease, will also dictate the choice of primary and secondary study endpoints. In particular, if young (<5 years of age) are being recruited, functional measures ought to be considered as primary outcome. Examples of motor function assessed by a motor function scale with demonstrated high intra-inter rater reliability are the Hammersmith functional motor scale for children that do not walk [42], the GMFM motor scale [http://bluewirecs.tzo.com/canchild/patches/GMFMScoresheet.pdf], and the French MFM motor scale [http://www.institut-myologie.org/escale/upload/pdf/Manuel-Utilisateur-MFM.pdf]. Strength should be considered as secondary outcome measure. The use of hand held myometer or QMT (on one side, grip, elbow flexor, knee extensor) are suggested. All agreed that the elbow flexor was the most reliable muscle group regardless of methodology. Theoretically, strength testing could be done using only this one muscle group. Strength measures can be used between ages 5 and 10 years and also in SMA type III patients that lose walking under age 10 years.

Secondary outcome measures should include respiratory measurements. For children older than 5 years spirometry including FVC (absolute values) can be used, together with the peak cough flow. The respiratory parameters suggested for SMA type I can be also used in SMA type II patients older than age 4 years such as the MPI (maximum inspiratory pressure) and the P100. The PedsQL was recommended as a quality of life measure. The Neuromuscular Module for the PedsQL has not yet been validated and is not available except on a collaborative basis. Such a collaboration should be worked out between AmSMART and the European group. A burden of disease measure for patient and care giver has not been used yet in patients with SMA.

5.3. SMA type III 

This group led by Kate Bushby established inclusion and exclusion criteria. The group agreed on the definition of SMA type III patients as walking patients, following the definition by the International SMA consortium (1992) [53]. SMA type III can be subdivided as IIIa/IIIb depending on onset before or after age 3 years, and also a possible further subgroup presenting after 12 years. These indicators could be useful for stratification at statistical analysis. A possible stratification for age could be between 3–16 and 17–60 years.

A consensus on inclusion criteria agreed that SMA type III subjects should be at least 3 years old, and able to walk for at least 10m without aid, they must have genetically confirmed disease by a SMN deletion/point mutation, and by SMN 2 copy number. Exclusion criteria should be participation in other trials, spinal surgery performed before or expected during the period of the trial, on serious coexistent pathologies, and pregnancy. It was confirmed that a wide consensus on standard care was important but that data were lacking to reach a general agreement. Primary outcome measures should be based on strength, measured by quantitative muscle testing or hand held myometry [54], or functional means such as time tests (duration of Gower's sign, 10m walking) or a Hammersmith scale for ambulant children used in Duchenne muscular dystrophy. Secondary outcome measures should include respiratory (FVC), elecrophysiological parameters (MUNE, CMAP amplitude), and DEXA scans. Follow-up should be at 6 and 12 months from baseline, and at 16 months after treatment. The validated quality of life questionnaire QOLPeds should also be considered.

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6. Trials for SMA in preparation 

Trials in preparation are summarized in Box 8., Box 9., Box 10., Box 11., Box 12., Box 13..

Box 8..
French RCT (randomized control trial) trial using riluzole in SMA II/SMA III

The French RCT (randomized control trial) trial using riluzole in 150 type II and III SMA patients (Brigitte Estournet) will start in spring 2005. The age range will be 6–20 years. It aims to prevent disease progression. There will be 11 participating centres. The study will be a double blind, placebo controlled, randomized design. Other inclusion criteria will be onset before age before 15 years for type III patients, and a functional score of at least 29/96. Exclusion criteria: spinal surgery one year before or 2 years after inclusion. Riluzole or placebo will be administered 50mg twice a day for 24 months. The patients will be tested every 3 months with blood tests, and the Mesure de Fonction Motrice pour les maladies neuromusculaires (MFM), FVC every 6 months and QOL yearly. The primary outcome measure will be the MFM. 204 patients have been followed up by the same centre for long periods and sing the MFM functional measure deterioration has been observed in all groups. A cumulative calculation revealed a linear 18% loss of function each 2 years. MFM is sensitive and easy to apply, and appears to be more responsive in younger ages. For type III patients the MFM does not show any change with time. FVC change is less sensitive than functional score.

Box 9..
Italian RTC using phenylbutyrate in SMA type II

The RCT study using PBA in 120 subjects affected by SMA II or non-ambulant III powered on a preliminary study [41] was presented by Eugenio Mercuri. The age ranged between 30m and 12 years, with 10 participating centres. Patients were recruited on the website by the 2 Italian associations. A total of 106 were enrolled and 92 finished the study, while 14 dropped out. Most frequent side effect were bad taste, drowsiness, vomiting, skin rash, headache and hallucinations. PBA was given in tablets at the dose of 500mg/kg per day in five doses, alternating weeks. The assessments post baselines were three. Some differences in outcome measures were used between 2 age groups: from 30 months to 5 years only HFMS as primary outcome measure was used, while for children between 5 and 12 years they used HFMS as primary outcome measure, and FVC together with hand held myometry as secondary outcome measures. Results are being analysed for differences between treated and untreated groups, variability in treated groups, and correlations with copy number. Open questions are whether 3 months are enough, if the dose is correct or it should be lower, which could be the best regimen rather than alternate weeks.

Box 10..
European Spinal Muscular Atrophy Randomised Clinical Trial (EUROSMART)

The ongoing European Spinal Muscular Atrophy Randomised Clinical Trial (EUROSMART) was presented by Haluk Topaloglu. This is a RCT of acetyl-l-carnitine in 110 SMA patients over age 5. The duration is 9 months. The primary efficacy variable is the increase in strength of handgrip and elbow flexion. Secondary variables are increase in knee flexion and extension maximum voluntary contraction, FVC and QOL. Also, increase in baseline forced vital capacity was examined. Training sessions for the examining researchers and intra-and-inter rater reliability were provided. Muscle strength was measured with a myometer in Newtons. Timed function tests included duration of Gower's sign and 10m walk. Assessments are made every 3 months. Participating countries are Germany (Voit and Schwake), Israel (Shapira), Italy (Merlini), Poland (Hausmanova-Petrusewitch and Jdrzejowska), Spain (Tizzano) and Turkey (Talim and Topaloglu). The lasts visit will be in in August 2005.

Box 11..
American open label trial with riluzole AMSMART

This open label trial with riluzole led by Susan Iannaccone, part of the AMSMART trial, is designed to demonstrate that riluzole is safe in infants less than age 2 years. The primary outcome is the age when 24h ventilation is need, and the age at death. Secondary objectives are to determine the reliability of the TIMP an infant motor scale, MUNE (motor unit number estimates) as an outcome measure in a multicentre study, PedsQOL (quality of life questionaire), to determine if SMN protein levels can be used as an outcome measure, and to correlate SMN copy count with SMA type. The study is not standardising respiratory care.

11 centres are each following 4 patients. Inclusion criteria:<24 months, genetic confirmation, SMN2 copy number>2. Exclusion criteria: able to sit>10s, other associated disorders, need for ventilation support>16h, previous riluzole intake. Each child is studied for 9 months, followed over 6 months and at 6 months drug is discontinued. Patients after withdrawn, repeat MUNE, TIMP, and PedsQOL. In addition, a MUNE reliability study is going on. Each EMG person examines 4 subjects: 3 normal adults, and one SMA at any age, then sends to the group in Utah for perusal, independent data recording and central recording. Fifteen patients will have estimations of the pharmacokinetics of riluzole; five patients for each three different age groups, on drug for 0 days, using heel sticks and urine levels for dosage. Since August 2004, 34/44 patients have been enrolled with MUNE, 8/11 completed the examination. For the drug trial, 11/44 enrolled. MUNE needs training and the right software. Standard of care is still very variable among centres. Other challenges include obtaining IRB approval and recruitment of patients. However, a well-funded trial increases family enthusiasm, and commits investigators and teams.

Box 12..
American SMA project cure

The SMA Project CURE was described by Kathy Swoboda. Two Phase 1/2 trials began in September 2003 using VPA in SMA type II or SMA III>2 years, and PBA in SMA children less than 2 years. Pilot trials were undertaken only at the Utah site, but seven participating centres are undergoing preparation for planned future multicentre trials. Natural history data evaluating a number of outcome measures were also reviewed. The functional motor assessment included HAMA (Hammersmith functional motor scale)>age 2 years, TIMP (test of infant motor performance) and CHOP TOSS (<2 years) for children younger that 2 years. Ongoing assessment of an SMA ambulatory functional motor scale which incorporates features of the HAMA, Gross Motor Function Measure (GMFM) and Hammersmith scale for ambulatory children with Duchenne Muscular Dystrophy has been undergoing additional modification and assessment in SMA ‘standers’ and ‘walkers’, due to ceiling effects of the HAMA for this population. Secondary assessments included whole body DEXA for lean and fat mass and bone density, PedsQOL, electrophysiological exams with MUNE (Motor unit number estimation) and CMAP (maximal compound muscle action potential) in a distally innervated hand muscle, SMN copy number, and quantitative real-time RT PCR of SMN mRNA and protein analysis via immunoblot from blood samples. Her group has examined more than 80 patients by these measures. HAMA has been shown to be reliable even as low as 2 years of age, but may have some floor and ceiling effects in weakest and strongest SMA II children. The results with HAMA are stable in all groups over six months. GMFM is much more unwieldy. In their experience a limited number of tests enhances reliability and acceptability. The MUNE & CMAP values are distinct between SMA I and III. MUNE does decrease with age, but is stable over up to 6 months envisioned for clinical trial purposes. In SMA type II, for which greatest numbers of patients are available, MUNE & CMAP show the most evident age/time relationship, with observations that this trend levels out by about 30 months. DEXA of whole body lean and fat mass is a reliable method but relevance or capacity for responsiveness in the short time intervals for clinical trials is not yet clear. The level of mRNA and SMN protein seems reasonably different between type I and II/III but their responsiveness to drug regimes is unknown. The dosage of SMN protein in platelets seems promising.

Box 13..
German RTC using VPA in SMA type 1

The outline of a planned multicentre randomized, placebo controlled double blind two-year VPA treatment trial of SMA I in Germany was presented by Thomas Voit.

VPA will be maintained at serum levels of 70–80mg/l. The primary outcome measure will be survival. Secondary outcome measures will be the functional status determined by Alberta infant motor scale, the rate of hospital admissions due to chest infections or the need for gastrostomy. All patients in the treatment and placebo groups will also receive carnitine. In order to study a homogeneous group, patients eligible should meet the following criteria: inclusion within 3 months after first doctor contact for SMA-related symptoms and not after age 6 months, two SMN2 copies. Exclusion criteria will be ventilator dependency at any time, intake of other potentially effective drugs and participation in other treatment trials. Power calculations showed that to prove 50% improved survival, i.e. an increase from 9 to 13.5 months on average, 130 patients had to be included. Because non-invasive ventilation would be an important intervening variable, 18h of NIV/day will be deemed equivalent to death for the analysis. The large sample size might make a European study desirable.

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7. Conclusions 

After two days discussion it became clear that future trials will have to be stratified with great attention, producing on one side a careful selection of patients and on the other matching the requirement of an adequate number of patients to accomplish the acceptable power for a randomized double blind controlled trial. Thus, everyone came to the agreement for the need of an international effort. The Workshop appointed a task force to harmonise Outcome Measures, and another separate task force to prepare guidelines on Standards of Care. Both forums were open to all the participants for sharing and adding information. It was also decided that the European effort will be shared with the American SMA organizations. Consequently, the forum on Outcome Measures was opened to all the American subcommittee on Outcome Measures led by Susan Iannaccone in order to use it for publication of statements on the topic. The Workshop agreed to support the Indiana University SMA register database but a possible European register was envisaged.

Throughout the Workshop ethical considerations were paramount and the parent patient representative input was highly valued.

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Acknowledgements 

This workshop was made possible by the financial support of the European Neuromuscular Centre (ENMC) and its main sponsors and associated members:


–Association Française contre les Myopathies (France)

–Deutsche Gesellschaft für Muskelkranke (Germany)

–Telethon Foundation (Italy)

–Muscular Dystrophy Campaign (UK)

–Muskelsvindfonden (Denmark)

–Prinses Beatrix Fonds (Netherlands)

–Schweizerische Stiftung für die Erforschung der Muskelkrankheiten (Switzerland)

–Österreichische Muskelforschung (Austria)

–Vereniging Spierziekten Nederland (Netherlands) and ENMC associate member:

–Associacion Española contra las Enfermedades Neuromusculares (Spain)

–Jenniffer Trust, USA Families of SMA, Italian Famiglie SMA are also acknowledged for support.

Workshop participants

Enrico Bertini (Rome, Italy)

Arthur Burghes A (Colombus, USA)

Kate Bushby K (Newcastle upon Tyne, UK)

Brigitte Estournet-Mathiaud (Paris, France)

Richard Finkel R (Philadelphia, USA)

Natahlie Goemans (Leuven, Belgium)

Susan Iannaccone S (Huston, USA)

Pierre Yves Jeannet (Lausanne, Switzerland)

Maria Jdrzejowska (Varsaw, Poland)

Audrey Lewis (Families for SMA, USA)

Marion Main (London, UK)

Anita Macaulay (Starford upon Avon, Jennifer Trust, UK)

Domenico Marchetti (Famiglie SMA, Rome, Italy)

Judith Melki (Evry, France)

Eugenio Mercuri (Rome, Italy)

Francesco Muntoni (London, UK)

Bernd Reitter (Mainz, Germany)

Anita Simmonds (London, UK)

Alessandra Solari (Milano, Italy)

Volker Straub (Newcastle upon Tyne, UK)

Kathryn Swoboda (Salt Lake City, USA)

Danilo Tiziano (Rome, Italy)

Edoardo Tizzano (Barcelona, Spain)

Haluk Topaloglu H (Ankara, Turkey)

Louis Viollet (Paris, France)

Thomas Voit (Essen, Germany)

Dick Willems (Amsterdam, The Netherlands)

Brunhilde Wirth (Cologne, Germany)

Klaus Zerres K (Aachen, Germany)

Richard Hughes (ENMC, Clinical Trial Network, London)

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PII: S0960-8966(05)00225-7

doi:10.1016/j.nmd.2005.07.005

Neuromuscular Disorders
Volume 15, Issue 11 , Pages 802-816, November 2005

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