| | Towards harmonisation of outcome measures for DMD and SMA within TREAT-NMD; Report of three expert workshops: TREAT-NMD/ENMC Workshop on outcome measures, 12th–13th May 2007, Naarden, The Netherlands; TREAT-NMD Workshop on outcome measures in experimental trials for DMD, 30th June–1st July 2007, Naarden, The Netherlands; Conjoint Institute of Myology TREAT-NMD Meeting on physical activity monitoring in neuromuscular disorders, 11th July 2007, Paris, FranceReceived in revised form 17 June 2008; accepted 11 July 2008. Article Outline• 1. Introduction • 2. Session 1 – extrapolation from work on preclinical models of disease and how preclinical studies can inform the development of clinical trials in DMD • 3. Session 2 – specific issues related to the planning of early clinical trials in DMD • 3.1. Design of proof of principle – first in man studies • 3.2. Clinically relevant endpoints • 3.3. Working together with the regulatory authorities to develop early clinical trials • 4. Session-3 – designing pivotal studies for NMD – outcome measures for SMA type I, II and III • 4.1. SMA type I • 3.2. SMA type II • 4.3. SMA type III • 5. Session 4 – functional scales used in Duchenne muscular dystrophy • 6. Session 5 – review of existing functional scales in SMA and DMD: a questionnaire-based study • 7. Session 6 – quality of life measures • 8. Session 7 – activity monitoring • 9. Session 8 – conclusions • 10. Session 9 – work in progress within TREAT-NMD and in collaboration with ICC and other groups • 11. Session 10 – closing remarks • 12. Workshops participants • 12.1. TREAT-NMD/ENMC Workshop on outcome measures, 12th–13th May 2007, Naarden, The Netherlands • 12.2. TREAT-NMD Workshop on outcome measures in experimental trials for DMD, 30th June–1st July 2007, Naarden, The Netherlands • 12.3. TREAT-NMD Meeting on physical activity monitoring in neuromuscular disorders, 11th July 2007, Paris, France • Acknowledgment • References • Copyright 1. Introduction  TREAT-NMD (Translational Research in Europe for the Assessment and Treatment of Neuromuscular Disease) is a European neuromuscular network aimed at strengthening European excellence in the treatment of rare inherited neuromuscular disorders (NMD) by reducing fragmentation and establishing a common road map for the progression of cutting edge therapies from laboratory to clinic. Defining and disseminating information on relevant outcome measures is the object of one of the work packages of TREAT-NMD (WP 9). The activities of this work package are focused on performing a systemic review of the available outcome measures and on the selection and elaboration of assessment tools to be used as outcome measures in clinical trials. A closely related activity looks at the application of these tools to specific diseases, and with the perspective of trials in Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA) being the most pressing, discussion of outcome measures relevant to these two diseases has been the first emphasis of these activities. Further details of all of these activities can be found at www.treat-nmd.eu. Since TREAT-NMD was initiated in January 2007 there have been a series of workshops and meetings followed up with discussions on the TREAT-NMD forum and via videoconferences. This report serves to summarise the recommendations and follow up work from three meetings. The first TREAT-NMD meeting on outcome measures was held to coincide with a European Neuromuscular Centre (ENMC) workshop on SMA. The scope of the meeting was to assess the application of functional scales in paediatric trials in DMD and SMA. The second meeting, organised with the support of TREAT-NMD and Duchenne Research Collaborative International (DRCI) and with the organisational support of the ENMC, gathered together 42 participants from nine Countries. The scope of the meeting was to assess the current situation with respect to outcomes measures for early trials in DMD. This multidisciplinary meeting was attended by participants from academia, clinicians, industrial representatives, regulatory authorities, charities and patient representatives. The main topics discussed were: the role of preclinical studies in the development of novel therapies for muscular dystrophy, early clinical trial design and the perspective of the regulatory authorities. Finally, a third meeting, jointly organised by the Institute of Myology and TREAT-NMD was convened to discuss activity monitors and to select possible models to record activity and endurance in daily activities and in longer-term multicentric studies. The outcomes of the meetings are presented relating to the stages of progression of trial planning and selection of outcome measures at each stage through the pathway from lab to clinic, from how the interpretation of studies in animal models impacts on trial planning, to the establishment of outcome parameters in early clinical trials, to the kinds of functional assessments that might be applicable in larger scale studies in SMA and DMD. This represents the first move towards a consensus on outcomes in these various situations. 2. Session 1 – extrapolation from work on preclinical models of disease and how preclinical studies can inform the development of clinical trials in DMD Animal models were considered in order to assess their pros and cons in preclinical studies. Much experience has already been generated on the use of different preclinical models for DMD, including the mdx mouse; the Golden retriever (GRMD) dog and the beagle dog models and on how preclinical studies can inform the development towards clinical trials. In terms of considering the way studies in these models can inform human trials, various questions were addressed; firstly, what are the advantages and disadvantage associated with these models when developing a new therapeutic approach; secondly; what is the best strategy to study these models and what to expect from therapeutic intervention. While each of these models represents an excellent tool to perform early proof of concept studies (for example restoration of dystrophin expression using antisense oligomers; or drugs to suppress nonsense mutations) all of these models have their own limitations as they do not completely recapitulate the disease course observed in humans. A drug development programme has to take into account these limitations which may be intrinsic to the specific species studied (such as the mild phenotype observed in mdx mice); others, such as the very considerable clinical variability observed in the dystrophic dogs, are less well understood and predictable. The variability of the clinical severity of these dog models make them difficult to use for clinical trials, while they represent excellent models for proof of concept studies. The reduced variability of clinical severity in the beagle compared to the GRMD, together with his smaller size makes this potentially a better model to study, however the clinical features of this model are still significantly variable. While issues such as scaling up of dosing can be assessed in these models, assessing functional outcomes of therapeutic interventions and applying the stringent statistic required in human randomised clinical studies can be more problematic. In addition to the intrinsic limitations of these models, there is also no experience yet related to successful therapies in preclinical models which have led to a successful therapy in patients with muscular dystrophies. Thus there is no experience on how to relate a force improvement in one of these preclinical models into functional benefit for DMD boys. This hopefully will be overcome when we start to have effective therapies. In respect of the various experimental protocols to assess the extent of the skeletal muscle “rescue” of treated animals, different protocols exist, and there is the need to use agreed and standardised standard operative procedures (SOPs). Two related initiatives are collaborating to take this discussion forward, led by TREAT-NMD (Santhera Pharmaceuticals and University of Basel) and by the Washington Wellstone Centre with NIH support. The outcome of these workshops will be published shortly and interim reports can be found on the TREAT-NMD website. Early involvement of the regulatory agencies is important when working at a programme of drug discovery using preclinical models, especially regarding the level of evidence required from the preclinical models before unnecessary and costly studies are undertaken in multiple models. 3. Session 2 – specific issues related to the planning of early clinical trials in DMD This is a multifaceted and complex issue and discussion was deliberately focused on a few areas where experience is accumulating. The first related to the difference in the path of development of an experimental therapy for rare neuromuscular disorders which can be considered orphan indications compared to the typical path regarding large scale drug therapies, with the usual progression from phase 1 clinical trials to 2 and 3. Part of the discussion focused on the need for SOPs for some of the assessment of therapeutic success in clinical trials; and on the development of surrogate measures of therapeutic success; finally a significant part of the discussion was focused on how to define and choose clinically relevant endpoints. 3.1. Design of proof of principle – first in man studies For the design of early proof of principle – first in man experiments, the importance of a staged approach in which initially mainly or only safety issues are addressed rather than efficacy was emphasised. Trying to measure clinically relevant efficacy endpoint following a relatively limited or regional intervention in a small number of patients is meaningless and this area should be approached with caution as it can lead to misunderstanding. Therapeutic development in the area of gene and stem cell therapy are much more complicated when compared to drug therapy, and the need to progress very carefully from small pilot studies assessing local safety to studies focused on regional safety before considering systemic studies was discussed in detail. These sequential steps, in which specific questions about immune tolerance are addressed, may take much longer compared to the development of drug based therapeutic strategies. This is an important issue for dissemination and communication when informing patients of the prospects of treatments coming into the clinic. Once again the importance of discussing as early as possible the planned therapeutic intervention with the regulatory authorities was emphasised. The evidence regarding the risk benefit ratio of different interventions is a complex one; while extensive safety preclinical testing is often necessary, the rationale for this testing and the probability that it will reduce the risk of adverse events in the patient population studies needs to be carefully appraised. In reality this means that the patients studied in these proof of concept studies need to be very carefully assessed in order to understand if any of the planned intervention has any adverse effect. The need to carefully collect data and learn from the experience of others involved in early clinical trials was also discussed. Early studies of new therapies in DMD are now in progress or complete. Prosensa’s experience with direct injection of 2-O-methly antisense oligonucleotides against exon 51 was very encouraging [1]; the PTC124 phase IIa study is also now completed, while the study using a morpholino molecule is currently underway in UK. These studies and other ongoing studies are providing essential information on aspects which are not usually well studied, such as the incidence of revertant fibres; the possibility that these could accumulate with age; but also the correlation between muscle imaging using MRI and muscle histology in dystrophic muscle. The importance was stressed of having robust methodology and a clear aim of testing the relevant hypothesis first, ensure adequate drug exposure, and explore the relevance of the chosen endpoints for future pivotal studies. Each of these early trials provides useful information which can inform future developments and early proof of concept studies should use similar endpoints to assess their local efficacy. Muscle biopsy may be an important investigation to check for restoration of dystrophin: so the interpretation of small amounts of dystrophin which can be expected as a result of early therapeutic interventions is particularly important but such analysis is not trivial. Semiquantitiative immunolabelling techniques using appropriate marker proteins (such as spectrin) are been independently developed in at least three labs. Quantification of low levels of dystrophin down to 2–5% can also be shown by Western blotting, but the technique is labour intensive and requires careful controls, both in terms of the amount of total protein in the sample and the amount of actual muscle protein. Experience of the various labs in this area will be shared to develop standardised operating procedures. A question which remains is the role of biopsies pre and post treatment for early trials. There is some evidence that there is no increase in revertant fibres with time so that perhaps a stored clinical diagnostic biopsy could be a valid comparator removing the need for a pre-treatment biopsy, but how generally referable this might be is not yet clear. This is an issue for ethical review, but also crucial for trial design and determining the validity of the ultimate results of early studies. In defining surrogate measures of therapeutic intervention, much additional work is needed. Only very few outcome measures have been shown to clearly correlate with disease progression; and little is known about the correlation of various biomarkers to events that are clinically meaningful to the patient. While it would be desirable to have biomarkers that track progression and response to treatment of the disease, these are at the moment of limited use. As a non-invasive method for monitoring treatment efficacy, MRI has promise: progression can be demonstrated with time and regions can be identified and quantified relative to fat and water phantoms. There are areas for more work in terms of benchmark data, standard operating procedures and consensus for data analysis. Strengths of the technique include the possibility to look at distribution of pathology, pathophysiology, anatomical correlation and monitoring of therapies. Blood RNA profiling is at an early stage and greater numbers are needed to validate early studies. Serum protein profiling is another approach where results are being generated. A biomarker development programme in France may generate leads which should be pursued on a collaborative basis. 3.2. Clinically relevant endpoints Several groups which participated at the workshop have developed highly accurate instruments to measure individual aspects of disease progression (quantitative muscle testing; myometry; a number of different functional scales). However only limited information is available regarding how these measures correlate with “life-limiting events” which are relevant for patients with neuromuscular diseases. Without these data it is difficult to assess the relevance of changes in performance on myometry or functional scales, or timed test performance of activities. While a lot of emphasis in the past was placed to promote one method to assess function or strength, the more important question relates to how specific measures of either function or strength correlate with “life-limiting events”. This is a relatively new concept, which however is now starting to be addressed by several groups. Data from the Cooperative International Neuromuscular Research Group shows that muscle strength measurement is a relevant surrogate measure for DMD trials and results from Pompe disease show that quantitative muscle testing correlates with disease duration, loss of muscle function, and physical function correlated with quality of life. There is a growing interest in the use of activity monitoring (see below) and tests such as the 6-Minute Walk Test [2] have now been adopted by different studies [3], [4], [5], [6]. Correlation with other measures such as functional scales and longitudinal data are necessary. For the identification of trial design to satisfy regulatory authorities, endpoint selection is crucial. Clinically meaningful endpoints have to have obvious value to the patient and define how the patient feels, functions or survives. Surrogate measures are a substitute for clinical benefit and may not have an immediate value to the patient. Forced vital capacity (FVC) could be an example of this. An ideal pivotal trial will have a mixture of these kinds of endpoints. Prior use in other pivotal studies can be an advantage at the regulatory level. 3.3. Working together with the regulatory authorities to develop early clinical trials When considering an early drug/therapeutic development program, it is important to engage as early as possible with the regulatory authorities. As it can be expected, the regulatory authorities such as European Medicines Agency (EMEA) and the US Food and Drug Administration (FDA) will have a relatively limited knowledge on specific rare neuromuscular conditions; however will have extensive knowledge on different requirements for a successful product development. Dialogue with the authority is therefore essential, and should be seen as a mutually necessary and advantageous process. There is a clear need for the neuromuscular community to reach consensus on validation and acceptance of relevant endpoints for trials, in particular with reference to their relationship with aspects of disease progression. Such a consensus, which is the aim of such organisations as TREAT-NMD and the International Coordinating Committee (ICC), will help to overcome bureaucratic hurdles to progress in trial development. 4. Session-3 – designing pivotal studies for NMD – outcome measures for SMA type I, II and III As potential therapies move from early trials to trials where there is the need to demonstrate therapeutic efficacy, new challenges need to be faced. Many of the existing outcome measures utilised in paediatric practice have been shown to be reliable and valuable tools in clinical settings but are not always feasible for research studies. The analysis of published trials on mainly paediatric patients with SMA has strongly suggested that the type of disease is the major determinant of the choice of outcome measure. No one scale can be regarded as relevant across the entire spectrum from babies with severe type I SMA to adults with mild disease. 4.1. SMA type I A new scale has been developed by Allan Glanzmann (Philadelphia) in collaboration with European Centres (Rome, London) for weak infants with type I SMA (CHOP-INTEND). The scale assesses both movement and function in very weak infants and can be used from birth to around 18 months of age. The validation of the scale is about to be published and training videos have been made available to the participants of the workshop. Any trial in SMA type I should take into account the natural history of the condition: unfortunately available data on natural history and early prognostic markers of severity of SMA type I are scanty. Cohorts of patients with SMA type I from Holland, Italy and Germany showed similar trends of survival and progression of the disease though inclusion criteria were similar but not identical. It was agreed that the data available could be re-evaluated according to similar inclusion criteria and collated in a large database that may provide information on early prognostic markers in untreated children. It was also agreed that there may be scope to develop a further prospective dataset based on the newly adopted standards of care [7]. The definition of prognostic indicators within SMA type I will be crucial for the execution of successful clinical trials. 3.2. SMA type II For the evaluation of SMA type II several individual scales have already been used in trials or in clinical practice. Marion Main (UK) presented data on the development and validation of the Hammersmith Functional Motor Scale for non-ambulant SMA children [8]. The scale has already been validated outside the UK [9] and used in two clinical trials using phenylbutyrate [10], [11] and in the ongoing trial using valproate in the States. Some criticisms of the scale (lack of detailed instructions, order of the items) appear to be largely solved by a US modified version [12]. The main problems highlighted in the discussion related to floor and ceiling effect in patients with borderline type I/II or type II/III, respectively. There have been various suggestions to overcome these difficulties by having add-on modules for upper limbs in weak children or using modules of items selected by existing scales such as the Gross Motor Function Measure (GMFM) [13] recently published [14], or adding items selected from functional scales used in ambulant DMD boys such as the Hammersmith Scale for Assessment of Motor Ability for ambulant DMD children [15] or the North Star Ambulatory Assessment. This will be further investigated by the participants. Elena Mazzone (Italy) proposed a list of items that are being used in an attempt to develop a module assessing upper limb function in weak infants. The items have been made available to the other participants to the workshop. Carole Beràrd (France) presented her data on the use of the Motor Function Measure (MFM) in SMA type II. The scale has been validated and is already in use within and outside France and offers a wide range of items assessing different domains in both ambulant and non-ambulant patients [16], [17]. This scale has the great advantage of being well validated and it can assess a wide range of abilities that could be extremely useful in long-term trials during which patients may undergo major change to their functional status. The perceived disadvantages of the scale are mainly related to the length of the examination and to the scoring system that may not be sensitive enough to detect small changes. Birgit Steffensen presented a Danish scale (the Egan Klassification (EK) scale) that provides useful information on everyday functional abilities in severely disabled patients with neuromuscular disorders. The scale is validated with respect to both DMD and SMA and has been shown to be strongly related to muscle strength and forced vital capacity in both diseases [18], [19], [20]. It has been proposed that the scale, largely used to date in DMD, may be used and possibly further developed for SMA as well. The scale has been made available to all the participants with the aim of collecting some data in SMA children that could help in better understanding its value and possible changes. 4.3. SMA type III There is less experience in the use of outcome measures in SMA type III. While there is some published evidence of the value and reliability of hand held myometry in patients with SMA type III [21], less attention has been devoted to functional scales. There is some experience of the use of existing scales such as the GMFM in US, or the Hammersmith Scale for Assessment of Motor Ability for ambulant DMD children [15] or North Star Ambulatory Assessment in UK, but no systematic study has been performed to validate any of these tools in such cohorts. A systematic review of retrospective data available and the collection of new data using the existing scales have been strongly encouraged in order to better understand the value of each scale and possible changes. 5. Session 4 – functional scales used in Duchenne muscular dystrophy Carole Beràrd (France) presented data on the use of the MFM scale in DMD. The MFM covers the whole range of abilities in both ambulant and non-ambulant DMD and it is also useful for weak older DMD boys who may need a more dedicated assessment of upper limb function [16]. The main advantage of providing the whole range of motor function is that the scale can be used in long-term studies in which patients may lose ambulation or become significantly weaker. It has however been discussed that, as discussed for SMA type II, the scoring system may not provide an accurate estimate of minimal changes. Elaine Scott (UK) presented data from a UK network using the North Star assessment, developed as a modification of the Hammersmith Scale for Assessment of Motor Ability for DMD. This scale includes 17 items and has several advantages compared to the previous Hammersmith scale for DMD including timed items and items reflecting changes such as the ability to run or jump that were not included in the previous version and could give rise to a ceiling effect in steroid treated individuals. The scale has been validated in UK and has an excellent intra and inter-observer reliability. This scale has been mainly designed for ambulant DMD boys or for those who have just lost ambulation and is not very sensitive for weak, non-ambulant DMD boys. Julaine Florence (US) gave a comprehensive review of measures of strength and other timed items (6-Minute Walk Test, walking 10 m etc.) and of their use in clinical trials highlighting the need for measures that fulfil the FDA/EMEA criteria which are increasingly emphasising the need for outcome measures that have a “life-altering” effect. In general it was felt that other measures should be considered such as the use of activity monitors (accelerometers, pedometrers etc.) and many of the people involved in the workshop volunteered to create a working subgroup exploring the various options and setting up small pilot studies to establish and compare their value (see Section 9). 6. Session 5 – review of existing functional scales in SMA and DMD: a questionnaire-based study Anna Mayhew (SMA representative, UK) gave an exhaustive overview and critical appraisal of the available functional outcome scales used in SMA and DMD and some results of a preliminary questionnaire circulated before the meeting investigating what experts thought about the applicability of individual scales currently available. The scales covered were: •Hammersmith Functional Motor Scale for SMA (HFMS) •Modified HFMS, Motor Function Measure (MFM) •Gross Motor Function Measure (GMFM) •The Hammersmith Scale for Assessment of Motor Ability (HAMA) •North Star Ambulatory Assessment (NSAA) •Egan Klassification scale (EK) Respondents were asked questions relating to the use of these tools, how they were perceived to be applicable in research and for clinical appropriateness and time taken to complete. Questions most often used a Likert scale (1–9) to gauge responses which allowed for objective analysis. The questionnaire was sent out via e-mail prior to the workshop to the circulation list of those attending the workshop. Twenty questionnaires were sent out to attendants of the workshop Representatives who returned the questionnaire came from US, France, Italy, Denmark, UK and Sweden. These included physiotherapists, medics, statisticians and geneticists. The questionnaire was passed on by some individuals to clinicians who had appropriate experience. Sixteen questionnaires were returned (80% return rate). Respondents were also asked whether they used the scale clinically, which conditions they felt is was appropriate to use with and what stage of the disease it applied to – ambulant or non-ambulant stage. The results are presented in Table 1. There was good representation of clinicians using all of the scales. Some scales were more generic, others more specific both in terms of the disease they were most appropriate for and also the stage of the disease they were designed to cover. | | |  | Specific or generic in nature | |
|---|
| Measure | Number using it clinically N=16 | Conditions most relevant to | Non ambulant/ambulant | Median | Range | Comments | |
|---|
| HFMS | 9 | SMA II, weak SMA III | Non-ambulant | 8 | 6–9 | Condition specific, moderate agreement | | | M-HFMS | 6 | SMA II, weak SMA III | Non-ambulant | 8 | 6–8 | Condition specific, moderate agreement | | | MFM | 8 | NMD | Both | 2 | 1–6 | Generic tool, moderate agreement | | | GMFM | 8 | CP, SMA II, III, DMD | Both | 6 | 1–8 | Equivocal, no agreement | | | HAMA | 11 | DMD, others | Ambulant borderline | 8 | 5–9 | Condition specific, moderate agreement | | | NSAA | 5 | DMD, SMA III | Ambulant | 8 | 6–9 | Condition specific, moderate agreement | | | EK | 9 | SMA, DMD | Non-ambulant | 6 | 1–9 | Equivocal, no agreement | | | | |
In the following section respondents were asked if they were using the scales clinically and how condition specific did they think each test was. The HAMA, HFMS, M-HFMS and the NSAA were all considered condition specific whereas the MFM was considered a generic tool. For the EK and the GMFM there was poor agreement and the scales were considered neither specific nor generic (Table 1). Respondents were then asked whether they considered the assessment to be a robust measure suitable for research. Generally tools were considered robust in nature (median⩾7 for EK, GMFM, HAMA, HFMS, M-HFMS and NSAA). Respondents were finally asked whether they considered the assessment to be a clinically relevant tool. All assessments accept the GMFM and MFM were considered to be clinically relevant. They were also asked how long on average the assessment took to complete. The two assessments that were considered quite lengthy were the GMFM and the MFM which both took approximately 45min to complete. All the other assessments took 20min or less. A list the advantages and disadvantages of the different tools was also required at the end of the questionnaire. The comments which occurred more than once are summarised in Table 2. Details of the questionnaire can be found at TREAT-NMD website, and a follow up questionnaire with participation from a focussed group of experts was set up to develop this further. 7. Session 6 – quality of life measures In a session on quality of life in paediatric neuromuscular disorders Linda Haynes (US) presented some preliminary findings on the validation of the Paediatric Quality of Life Inventory (PedsQL) add-on module for neuromuscular disorders. So far this is the only questionnaire available which allows for disease specific measures to be applied to neuromuscular patients and there have been interest from different participants and by the TREAT-NMD to discuss translation in different European languages and subsequent validation in both SMA and DMD. Sonia Messina (Italy) presented some preliminary results of another questionnaire (SOLE) specifically developed for children with neuromuscular disorders by a group in Pavia (Italy). The questionnaire was developed specifically for young children with neuromuscular disorders and includes a series of vignettes representing daily activities and other activities related to the disease, such as going to hospital etc. The format of the questionnaire, using stickers with different face expressions (smiling, neutral, sad) makes the test very suitable for young children. The test is being validated in Italy as part of a multicentric study involving over 130 patients. 8. Session 7 – activity monitoring While validated measures of muscle strength and function exist, these do not provide insight on patients’ endurance and only give a generic perspective of the correlations between patients’ strength and functioning in the day-to-day life. The measurement of activity using activity monitors is a rapidly expanding area; a few activity monitors, such as pedometers and accelerometers, have been developed and validated in children. However their role in clinical and research settings in patients with neuromuscular disorders has still to be delineated and this was discussed in a one-day meeting in Paris. Sonia Messina (Rome) provided a brief review of activity monitors highlighting pros and cons of the available models. Accelerometers are electronic devices that specifically measure accelerations produced as a body segment or limb part moves through space. Some of the accelerometers are unidimensional or single-plane devices while others, employs a two-plane sensor specifically designed for the accelerations of the ankle during walking or are multidimensional, capable of recording movements in all planes. Most of the available accelerometers are provided of programmability of sampling epochs of motion. There are two models of accelerometers currently commercially available that appear to be most suitable for clinical studies in neuromuscular disorders. The StepWatch Activity Monitor (SAM, Cymatech, US) is a small, lightweight, accurate, unobtrusive device that measures frequency, duration, and intensity of activity. It has an advantage over pedometers because it records step-rates at predetermined intervals that begin as low as 6s. Its advantage over other accelerometers is that it accurately records steps taken by subjects with whose gait characteristics vary widely [22], [23], [24]. SAM has been used in pediatric populations of typically developing youths in the age groups five to 21 years showing an excellent accuracy when compared with directly observed steps (correlations between 0.96 [25] and 0.99 [22], [23]). Recently a new tool has been proposed, the SenseWear arm-band (BodyMedia, US). This two-axis accelerometer is able to calculate and report data on metabolic profile such as on activity profile. It has been used to measure energy expenditure in healthy subjects [26] and in patients with metabolic [27] and cardiac disorders [28]. This device has not yet been used in children but has the advantage that can be used in non-ambulant patients on their arms and provides information on the time spent lying horizontally or sitting and on the activity in each posture. Yves Pierre Jeannet and Kamiar Aminian presented a device developed in Lausanne (Médecin Associé, MER, Lausanne) that is currently used in patients with Duchenne muscular dystrophy. They reported a pilot study investigating daily functional ability of Duchenne (DMD) patients and healthy controls using a small and light, wireless ambulatory system (ASUR) attached to the child’s t-shirt. ASUR is composed of three accelerometers and one gyroscope which identify body postures (Lying, sitting and standing) and periods of walking. They demonstrated that the daily physical activity of ambulatory myopathic children can be reliably and precisely monitored and measured in their home environment providing a detailed picture of the child’s physical activity throughout the day. This new model has an interesting potential, as it has been specifically designed for neuromuscular disorders, but it is still not commercially available and is undergoing further developments. Julaine Florence reported the experience on activity monitors in the main neuromuscular Centres in US. A quantitative measurement of DMD patients’ daily ambulation has been investigated by McDonald et al using the SAM [16]. In this study 16 ambulatory DMD patients (age range 5–13 years) and 20 controls were investigated during 3 days of daily activity. DMD subjects, when compared with controls, had significantly more inactive minutes, took significantly fewer steps and spent fewer minutes performing intermittent or fast walking. The study concluded that step-rate monitoring with the SAM provides useful outcome measures with which to evaluate the activity of ambulatory boys with DMD. The SAM is currently being used in documenting step activity in a longitudinal, multi-center natural history study in DMD and as an outcome measure in therapeutic trials in both DMD and Myotonic Dystrophy. Although, this study gives important insights into the activity pattern in DMD, the technology used does not provide any temporal assessment of the body postures. Further discussions focused on the two models that more likely are going to be used (the “Step Activity Monitor” and the “Sense-wear arm-band”) and on the planning of a common project for their validation. Two centers (Rome and London) volunteered to try SAM and Sense-wear arm-band in ambulant and non-ambulant patients with SMA and DMD in order to obtain more background information on their reliability and reproducibility before planning a multicentric pilot longitudinal study. 9. Session 8 – conclusions 1.A dialogue between the stakeholders in the process of trial design in NMD (clinicians, industry, patients and their representatives and the regulatory authorities) is crucial to advance conclusions in this area. 2.Interpretation of preclinical studies needs to take into account the specific advantages and limitations of the animal models used. Standardisation of the techniques used to study these models will provide some guidance as to their interpretation as well. The regulatory authorities should be included in the discussion process on preclinical as well as clinical studies so that unnecessary studies are not performed. 3.The design of early clinical trials relates more to proof of principle and safety than efficacy. Sharing experience from these rare studies is important to move the field forward. 4.In planning pivotal studies of efficacy, attention to the impact on patients of modification of the disease progression is important for engagement of the regulatory authorities. Various functional scales exist and will be disseminated via TREAT-NMD, while applications of other measures such as daily activity and endurance is likely to become more important for their direct impact on disease experience by the patient and family. 5.A range of validated functional outcome measures already exist which are ready for application in trials of SMA and DMD. All tools had strengths and weaknesses and lack of correlation of such functional scales with progression of disease means that their relationship to disease milestones has yet to be fully defined. 6.The choice of appropriate functional outcome measures will depend on the circumstances of the particular trial, such as the disease treated the level of disability of the participants and length of the trial. Tools which are specific to condition and stage of disease were generally regarded as more sensitive to change but had inherent drawback such as ceiling or floor effects. More generic tools avoided these floor and ceiling effects but perhaps lacked sensitivity. 7.There are areas where some of the measures could be further developed. Disease specific add-on modules, such as the proposed one on upper limb for weak SMA type II or DMD or an extension module for non-ambulant SMA type II should be considered end encouraged. 8.As centres will most likely be asked to utilise different measures in different trials, it is essential that outcome measures have robust manuals and means for training. Manuals and training videos will be made available via the TREAT-NMD website as will access to specialised training courses. 9.Functional scales are excellent clinical tools but may be less relevant in ambulant patients and other tools that also assess endurance and everyday activities should be explored. 10.More effort should also be put into the identification of measures that can predict ‘life altering events’ or that could be ‘clinically meaningful’, as suggested by FDA. For example, use of the 6-Minute Walk Test as an outcome in neuromuscular diseases is being explored by several groups. 10. Session 9 – work in progress within TREAT-NMD and in collaboration with ICC and other groups 1.Generation of SOPs for animal model assessment. This work is well advanced and a publication is due for submission in summer 2008. 2.Completion of a registry of outcome measures in NMD. Work is advanced on the generation of a registry of outcome measures used in NMD which will act as an online resource for the community. 3.Validation of 6-Minute Walk Test in DMD. This measure has been recently been suggested by the FDA as a reliable indicator of functional changes and has been chosen as the primary clinical measure in the ongoing study of PTC124. Reliability tests and cross validation with other scales (North Star, timed items etc.) are currently in progress. 4.Identification of early predictors of life altering events. Retrospective and prospective studies are encouraged to establish the value of timed items or functional scores to predict life altering events such as loss of independent ambulation in DMD. 5.Value of skeletal muscle MR as an outcome measure for Clinical Trials. Although muscle MRI is increasingly used as a diagnostic tool in the identification of patterns of muscle involvement in genetically distinct muscle diseases, its use as an outcome measure in neuromuscular disorders is still limited. This is partly related to the lack of longitudinal normative data illustrating changes in muscle structure as part of the natural history of the disease; the complexity of interpreting changes in children where several processes (physiological growth and progressive muscle involvement) take place simultaneously and more generally to the lack of clear protocols on data acquisition and collection. A workshop has been planned at the end of 2008 to harmonise preliminary work that is currently ongoing in Paris, Newcastle, London and other centres and to reach a consensus with US centers that have recently held a similar workshop in Bethesda. 6.Engagement of the regulatory authorities in trial design. Together with the ICC and charities across the world including the JTSMA and SMA Europe, a meeting is planned for October 2008 to explain the specific challenges of choice of outcome measures in SMA. Further consensus will be generated ahead of this meeting via a meeting in Boston in June 2008. 11. Session 10 – closing remarks An important achievement of these meetings was the realisation that now that increasing therapeutic targets are on the horizon, there will be increasing pressure on time, funding, availability of key players and even patients unless an informed approach to the decision making of which strategy to take forward is achieved. It also became apparent that translational research is a different concept from other aspects of hypothesis driven research, with which most investigators are more familiar. A translational research project should not be handled in the same way as another research study, and a paradigm shift is necessary in order to take translational research forward both at the preclinical and the clinical levels. Clear milestones driven projects with robust go-no-go decision making steps are necessary to be successfully embarked in a project of therapeutic development. A successful therapeutic development project should involve very early on direct involvement of academia, the industry, advocacy groups and regulatory authorities. 12. Workshops participants 12.1. TREAT-NMD/ENMC Workshop on outcome measures, 12th–13th May 2007, Naarden, The Netherlands E. Mercuri (Italy) (chair), A. Ambrosini (Italy), C. Beràrd (France), E. Bertini (Italy), K. Bushby (UK), J. Cobben (The Netherlands), M. Eagle (UK), J. Florence (US), A. Glanzmann (US), L.S. Hynan (US), M. Main (UK), A. Mayhew (UK), E. Mazzone (Italy), S. Messina (Italy), F. Muntoni (UK), S. Rudnik-Schoeneborn (Germany), B. Steffensen (Denmark), K. Swoboda (US), M. de Visser (The Netherlands), T. Voit (France). 12.2. TREAT-NMD Workshop on outcome measures in experimental trials for DMD, 30th June–1st July 2007, Naarden, The Netherlands R. Griggs (US) (Chair), A. Ambrosini (Italy), L. Atkinson (US), S. Braun (France), K. Bushby (UK), D. Caizergue (France), J. Christensen (US), G. Cossu (Italy), V. Cwik (US), K. Davies (UK), S. Del Signore (UK), P. Denefle (France), M. Denti (Italy), G. Elfring (US), D. Escolar (US); K. Flanigan (US), P. Furlong (US), E. Heslop (UK), S. de Kimpe (The Netherlands), R. Korinthenberg (Germany), H. Laouenan (France), S. Lynn (UK), J. Marler (US), T. Meier (Switzerland), E. Mercuri (Italy), L. Miller (US); F. Muntoni (UK), G.J. van Ommen (The Netherlands), T. Partridge (US), J. Porter (US); G. Spinella (US), S. Takeda (Japan), S. Tapscott (US), J. Tinsley (UK), Y. Torrente (Italy), J. Tremblay (Canada), E. Venneker (The Netherlands), J. Verschuuren (The Netherlands), J. Scott (US), V. Straub (UK), A. Urtizberea (France). E. Vroom (The Netherlands), D. Wells (UK), B. Wong (US). 12.3. TREAT-NMD Meeting on physical activity monitoring in neuromuscular disorders, 11th July 2007, Paris, France T. Voit (France) (Chair), K. Aminian (Switzerland), M. Eagle (UK), J. Florence (US), Y.P. Jeannet (Switzerland), M. Main (UK), A. Mayhew (UK), E. Mazzone (Italy), E. Mercuri (Italy), S. Messina (Italy), F. Muntoni (UK). 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