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OPTIMISTIC Résumé de rapport

Project ID: 305697
Financé au titre de: FP7-HEALTH
Pays: Netherlands

Periodic Report Summary 2 - OPTIMISTIC (Observational Prolonged Trial In Myotonic dystrophy type 1 to Improve QoL-Standards, a Target Identification Collaboration)

Project Context and Objectives:
Myotonic dystrophy type1 (DM1) is a rare, inherited, chronic progressive disease as well as an autosomal dominant multisystemic disorder. It is the most common adult form of muscular dystrophy, with a prevalence of approximately 10 per 100,000 people affected (Norwood 2009, Norman 1989). With 733 million people in Europe, we estimate that 75,000 people are DM1 patients in Europe (European Commission 2011).

Despite the huge impact of DM1 on the daily life of both patients and their family members in Europe, DM1 patients fail to receive the quality of healthcare that is available as they are not assertive users of the health care system. Recent developments in molecular therapies (e.g. by Prosensa in Europe, ISIS in the USA) are approaching clinical development. These potential therapeutics are mitigated against by the lack of validated clinical / surrogate biologically based outcome measures and the absence of a European clinical trial infrastructure in DM1 for future use (Blonsky 2012).

The aim of OPTIMISTIC is to improve clinical practice in the management of patients with this rare disease for which no dedicated treatment is currently available. OPTIMISTIC is a model-based (Fig. 1), multi-centre, randomised controlled trial designed to compare a two component tailored behavioural change intervention to increase physical activity against standard patient management regimes, with particular attention given to the definition of appropriate outcome measures and new clinical guidelines for DM1 management. The two components of the intervention are 1) cognitive behavioural therapy (CBT) and 2) graded physical activity and we will evaluate the intervention’s effectiveness and safety against standard patient management (Fig. 1, see attachment). Both interventions build on similar elements: CBT involves graded physical activity and graded physical activity makes use of a behavioural change programme.

Participants are recruited from myotonic dystrophy clinics and neuromuscular centres in France, Germany, the Netherlands and the UK. A total of 255 male and female patients aged 18 years and older with genetically proven classical or adult DM1 suffering from severe fatigue (only DM1 patients with a CIS subscale fatigue score > 35 are likely to benefit from the intervention), able to walk independently and able to complete the trial interventions have been included.

A key objective of OPTIMISTIC is to provide outcome measures that are relevant for the patients and have a rate of change that is appropriate for a clinical trial timeframe. In addition, OPTIMISTIC will identify genetic factors that predict outcome and potential biomarkers as surrogate outcome measures that best explain the observed clinical variation.

Project Results:
OPTIMISTIC aiming at improvement of clinical practice in the most frequent neuromuscular disorder (myotonic dystrophy type 1) has made substantive progress. This model-based (Fig. 1, see attachment) trial evaluates the effect and the maintenance of effects of cognitive behavioural therapy (CBT) and exercise training on the reduction of fatigue in these patients.
In the last period, the trial design was majorly improved, and thereby changed from a three-armed into a two-armed study. The reason was that during preparation of the trial we discovered that in practice both interventions build on similar elements: CBT involves graded physical activity and the exercise therapy makes use of a behavioural change programme. Both interventions started far apart years ago and now developed into a similar approach, based on optimal efficacy. The changed design improves the quality of the study in several ways: Increase adherence, more robust study design, in line with the latest insights of combining psychobiological interventions, optimal combined intervention to get a beneficial result for the patient.

The trial is ongoing in all 4 centres (The Netherlands, UK, France and Germany). In the 2nd period, all ethical and local approvals were achieved. We successfully discussed and managed the translation, backtranslation and harmonisation of the outcome measures. Standard operating procedures on material (blood) handling and MR muscle imaging were developed and applied in the various centres. CBT has been successfully applied in all centres after onsite training of CBT therapists. Recruitment of patients and all baseline data of all 255 patients have been finalized. We will complete the primary outcome data collection at the end of March 2016.

A website is in place, and three newsletters for patients in 4 languages have been published. In addition to the OPTIMISTIC website, we disseminate the newsletters via the TREAT-NMD and Muscular Dystrophy UK newsletters. The publication plan of the project has been discussed and accepted. Three telephone conferences with the external advisory board were organised to discuss relevant parts or critical issues, for example the OPTIMISTIC protocol, or recruitment and retention. The feedback was reported to the consortium. 4 consortium meetings in the 4 participating countries have been held.
Recruitment of patients (June 14, 2014) is largely as planned (Fig. 2, see attachment).

Potential Impact:
Based on our experiences until now, there is no reason to think that the expected final results and their potential impact will change.

Evidently, there is no one-dimensional one-strike solution to improve clinical practice in the management of DM1 patients. OPTIMISTIC, if accomplished, will have the following concrete impact:
1. OPTIMISTIC will lead to evidence-based clinical guidelines on exercise training and cognitive behavioural therapy in patients with DM1.
2. Develop clinically meaningful DM1 outcome measures for both routine clinical use and within the context of future clinical trials. This will lead to the more rapid assessment of the validity of putative treatments and decrease the time for the therapeutic to reach the patient. The adoption of these outcome measures in routine clinical practice will provide clinicians the tools in which to optimize the management of DM1 patients.
3. The creation of an European DM1 clinical trial framework by uniting strong DM1 clinical centres with experts in outcome measures and clinical trial management. This will facilitate the earlier uptake of novel therapeutics into clinical development for possible EMEA registration if successful.
4. The identification of isolated (serum, urine, muscle and genetic) and composite biomarkers that reflect both the disease status and treatment outcome. This will allow the stratification and early intervention in at risk groups.
5. Address scientific questions about the moderating and/or mediating factors of the short-term efficacy and maintenance of clinical response, and the short-term and long-term safety of the interventions.

The project will have further spin-off in areas outside those primarily targeted:
1. The acquired knowledge will also impact on the broader issue of exercise training and cognitive behavioural therapy in other neuromuscular disorders. This knowledge will inform and fuel research in the muscle – brain interaction: training the muscles in brain disorders (Parkinson’s disease, Alzheimer), and the brain (cognitive behavioural therapy) in muscle diseases.
2. Collaborating together in the proposed studies will strengthen the research infrastructure in the neuromuscular community within the EU, consisting of academic centres with high levels of expertise that will be able to undertake other collaborative studies.

Optimistic will answer these objectives by delivering:
1. The first trial of this type in Europe and therefore a major scientific impact in this field;
2. Develop better DM1 treatments;
3. Involving 255 patients and their families from the start of the project;
4. Involving four major clinical neuromuscular centres in Europe, with a potential to quickly reach 1000 patients;
5. Training through 5 workshops of 20 therapists up to 100 therapists from all Europe with the use of the new clinical guidelines developed in the project;
6. A coordinated effort with other initiatives on rare diseases in Europe and internationally (IRDiRC, EURORDIS rare diseases Europe, etc);
7. Delivering data to support improved health policy initiatives in DM1 clinical management;
8. A better public awareness on the disease amongst policy makers and the general public.

We will establish a multi-national clinical research effort (Fig. 3) with the following goals of i) informing clinical trial design, ii) identifying relevant outcome measures and potential biomarkers that reflect the disease state, iii) investigating the effect of exercise training and cognitive behavioural therapy on quality of life in DM1 patients, leading to accepted evidence-based clinical guidelines, iv) improving clinical practice in the management of DM1 patients. In addition, because antisense oligonucleotide therapies (such as developed by PROSENSA) are expected to reach the clinic for DM1 in the near term, an urgent need exists for outcome measures that have a rate of change that is appropriate for a clinical trial timeframe.

This approach is innovative by moving beyond the state-of-the-art in several respects. Additional to evidence-based knowledge on the effect of either of the interventions on DM1 patients, OPTIMISTIC will address the moderating and/or mediating factors of the short-term efficacy and maintenance of the clinical response, and the short-term and long-term safety of both interventions. This will improve our understanding of the relevant determinants of DM1 prognosis. This new knowledge will also be translated to new clinical guidelines for patient management. Patient perspectives and possible discrepancies with professionals will help to elaborate strong and weak points in the implementation of both interventions, which in turn might explain individual specific results obtained in the effect study.

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Informations connexes


Maarten van Langen, (Legal Advisor)
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Numéro d'enregistrement: 182371 / Dernière mise à jour le: 2016-05-23
Source d'information: SESAM