E-Health & Innovation to Overcome Barriers in Neuromuscular Diseases. Report from the 3rd eNMD Congress: Pisa, Italy, 29-30 October 2021.

Neuromuscular diseases (NMDs), in their phenotypic heterogeneity, share quite invariably common issues that involve several clinical and socio-economical aspects, needing a deep critical analysis to develop better management strategies. From diagnosis to treatment and follow-up, the development of technological solutions can improve the detection of several critical aspects related to the diseases, addressing both the met and unmet needs of clinicians and patients. Among several aspects of the digital transformation of health and care, this congress expands what has been learned from previous congresses editions on applicability and usefulness of technological solutions in NMDs. In particular the focus on new solutions for remote monitoring provide valuable insights to increase disease-specific knowledge and trigger prompt decision-making. In doing that, several perspectives from different areas of expertise were shared and discussed, pointing out strengths and weaknesses on the current state of the art on topic, suggesting new research lines to advance technology in this specific clinical field.

Acid α-glucosidase (GAA) activity and glycogen content in muscle biopsy specimens of patients with Pompe disease: A systematic review.

Pompe disease is a rare genetic disorder characterized by a deficiency of acid α-glucosidase (GAA), leading to the accumulation of glycogen in various tissues, especially in skeletal muscles. The disease manifests as a large spectrum of phenotypes from infantile-onset Pompe disease (IOPD) to late-onset Pompe disease (LOPD), depending on the age of symptoms onset. Quantifying GAA activity and glycogen content in skeletal muscle provides important information about the disease severity. However, the distribution of GAA and glycogen levels in skeletal muscles from healthy individuals and those impacted by Pompe disease remains poorly understood, and there is currently no universally accepted standard assay for GAA activity measurement. This systematic literature review aims to provide an overview of the available information on GAA activity and glycogen content levels in skeletal muscle biopsies from patients with Pompe disease. A structured review of PubMed and Google Scholar literature (with the latter used to check that no additional publications were identified) was conducted to identify peer-reviewed publications on glycogen storage disease type II [MeSH term] + GAA, protein human (supplementary concept), Pompe, muscle; and muscle, acid alpha-glucosidase. A limit of English language was applied. Results were grouped by methodologies used to quantify GAA activity and glycogen content in skeletal muscle. The search and selection strategy were devised and carried out in line with Preferred Reporting of Items in Systematic Reviews and Meta-Analysis guidelines and documented using a flowchart. Bibliographies of papers included in the analysis were reviewed and applicable publications not already identified in the search were included. Of the 158 articles retrieved, 24 (comprising >100 muscle biopsies from >100 patients) were included in the analysis, with four different assays. Analysis revealed that patients with IOPD exhibited markedly lower GAA activity in skeletal muscles than those with LOPD, regardless of the measurement method employed. Additionally, patients with IOPD had notably higher glycogen content levels in skeletal muscles than those with LOPD. In general, however, it was difficult to fully characterize GAA activity because of the different methods used. The findings underscore the challenges in the interpretation and comparison of the results across studies because of the substantial methodological variations. There is a need to establish standardized reference ranges of GAA activity and glycogen content in healthy individuals and in Pompe disease patients based on globally standardized methods to improve comparability and reliability in assessing this rare disease.

Continuous stellate ganglion block for ventricular arrhythmias: case series, systematic review, and differences from thoracic epidural anaesthesia.

AIMS: Percutaneous stellate ganglion block (PSGB) through single-bolus injection and thoracic epidural anaesthesia (TEA) have been proposed for the acute management of refractory ventricular arrhythmias (VAs). However, data on continuous PSGB (C-PSGB) are scant. The aim of this study is to report our dual-centre experience with C-PSGB and to perform a systematic review on C-PSGB and TEA. METHODS AND RESULTS: Consecutive patients receiving C-PSGB at two centres were enrolled. The systematic literature review follows the latest Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. Our case series (26 patients, 88% male, 60 ± 16 years, all with advanced structural heart disease, left ventricular ejection fraction 23 ± 11%, 32 C-PSGBs performed, with a median duration of 3 days) shows that C-PSGB is feasible and safe and leads to complete VAs suppression in 59% and to overall clinical benefit in 94% of cases. Overall, 61 patients received 68 C-PSGBs and 22 TEA, with complete VA suppression in 63% of C-PSGBs (61% of patients). Most TEA procedures (55%) were performed on intubated patients, as opposed to 28% of C-PSGBs (P = 0.02); 63% of cases were on full anticoagulation at C-PSGB, none at TEA (P < 0.001). Ropivacaine and lidocaine were the most used drugs for C-PSGB, and the available data support a starting dose of 12 and 100 mg/h, respectively. No major complications occurred, yet TEA discontinuation rate due to side effects was higher than C-PSGB (18 vs. 1%, P = 0.01). CONCLUSION: Continuous PSGB seems feasible, safe, and effective for the acute management of refractory VAs. The antiarrhythmic effect may be accomplished with less concerns for concomitant anticoagulation compared with TEA and with a lower side-effect related discontinuation rate.

Fascial plane blocks for cardiothoracic surgery: a narrative review.

In recent years, there has been a growing awareness of the limitations and risks associated with the overreliance on opioids in various surgical procedures, including cardiothoracic surgery.This shift on pain management toward reducing reliance on opioids, together with need to improve patient outcomes, alleviate suffering, gain early mobilization after surgery, reduce hospital stay, and improve patient satisfaction and functional recovery, has led to the development and widespread implementation of enhanced recovery after surgery (ERAS) protocols.In this context, fascial plane blocks are emerging as part of a multimodal analgesic in cardiac surgery and as alternatives to conventional neuraxial blocks for thoracic surgery, and there is a growing body of evidence suggesting their effectiveness and safety in providing pain relief for these procedures. In this review, we discuss the most common fascial plane block techniques used in the field of cardiothoracic surgery, offering a comprehensive overview of regional anesthesia techniques and presenting the latest evidence on the use of chest wall plane blocks specifically in this surgical setting.

EURO-NMD registry: federated FAIR infrastructure, innovative technologies and concepts of a patient-centred registry for rare neuromuscular disorders.

BACKGROUND: The EURO-NMD Registry collects data from all neuromuscular patients seen at EURO-NMD's expert centres. In-kind contributions from three patient organisations have ensured that the registry is patient-centred, meaningful, and impactful. The consenting process covers other uses, such as research, cohort finding and trial readiness. RESULTS: The registry has three-layered datasets, with European Commission-mandated data elements (EU-CDEs), a set of cross-neuromuscular data elements (NMD-CDEs) and a dataset of disease-specific data elements that function modularly (DS-DEs). The registry captures clinical, neuromuscular imaging, neuromuscular histopathology, biological and genetic data and patient-reported outcomes in a computer-interpretable format using selected ontologies and classifications. The EURO-NMD registry is connected to the EURO-NMD Registry Hub through an interoperability layer. The Hub provides an entry point to other neuromuscular registries that follow the FAIR data stewardship principles and enable GDPR-compliant information exchange. Four national or disease-specific patient registries are interoperable with the EURO-NMD Registry, allowing for federated analysis across these different resources. CONCLUSIONS: Collectively, the Registry Hub brings together data that are currently siloed and fragmented to improve healthcare and advance research for neuromuscular diseases.

104-week efficacy and safety of cipaglucosidase alfa plus miglustat in adults with late-onset Pompe disease: a phase III open-label extension study (ATB200-07).

The phase III double-blind PROPEL study compared the novel two-component therapy cipaglucosidase alfa + miglustat (cipa + mig) with alglucosidase alfa + placebo (alg + pbo) in adults with late-onset Pompe disease (LOPD). This ongoing open-label extension (OLE; NCT04138277) evaluates long-term safety and efficacy of cipa + mig. Outcomes include 6-min walk distance (6MWD), forced vital capacity (FVC), creatine kinase (CK) and hexose tetrasaccharide (Hex4) levels, patient-reported outcomes and safety. Data are reported as change from PROPEL baseline to OLE week 52 (104 weeks post-PROPEL baseline). Of 118 patients treated in the OLE, 81 continued cipa + mig treatment from PROPEL (cipa + mig group; 61 enzyme replacement therapy [ERT] experienced prior to PROPEL; 20 ERT naïve) and 37 switched from alg + pbo to cipa + mig (switch group; 29 ERT experienced; 8 ERT naive). Mean (standard deviation [SD]) change in % predicted 6MWD from baseline to week 104 was + 3.1 (8.1) for cipa + mig and - 0.5 (7.8) for the ERT-experienced switch group, and + 8.6 (8.6) for cipa + mig and + 8.9 (11.7) for the ERT-naïve switch group. Mean (SD) change in % predicted FVC was - 0.6 (7.5) for cipa + mig and - 3.8 (6.2) for the ERT-experienced switch group, and - 4.8 (6.5) and - 3.1 (6.7), respectively, in ERT-naïve patients. CK and Hex4 levels improved in both treatment groups by week 104 with cipa + mig treatment. Three patients discontinued the OLE due to infusion-associated reactions. No new safety signals were identified. Cipa + mig treatment up to 104 weeks was associated with overall maintained improvements (6MWD, biomarkers) or stabilization (FVC) from baseline with continued durability, and was well tolerated, supporting long-term benefits for patients with LOPD.Trial registration number: NCT04138277; trial start date: December 18, 2019.

Effect of avalglucosidase alfa on disease-specific and general patient-reported outcomes in treatment-naïve adults with late-onset Pompe disease compared with alglucosidase alfa: Meaningful change analyses from the Phase 3 COMET trial.

BACKGROUND: The Phase 3 COMET trial (NCT02782741) comparing avalglucosidase alfa and alglucosidase alfa included health-related quality of life (HRQoL) assessments in treatment-naïve patients with late-onset Pompe disease (LOPD). Here, we further characterize results from disease-specific and general patient-reported outcome (PRO) measures. METHODS: Adults who participated in the COMET trial receiving avalglucosidase alfa or alglucosidase alfa (both 20 mg/kg biweekly) during the 49-week double-blind treatment period were included in the analysis. Proportions of patients exceeding meaningful change thresholds at Week 49 were compared post hoc between treatment groups. PROs and their meaningful change thresholds included: Pompe Disease Severity Scale (PDSS; decrease 1.0-1.5 points), Pompe Disease Impact Scale (PDIS; decrease 1.0-1.5 points), Rasch-built Pompe-specific Activity Scale (R-PAct; change from unable to able to complete activity), 12-item Short Form Health Survey (SF-12; physical component summary [PCS] score: increase ≥6 points, mental component summary [MCS] score: increase ≥7 points), EuroQol 5 Dimension 5 Level (EQ-5D-5L; improvement of ≥1 category), and Patient Global Impression of Change (PGIC; any improvement). RESULTS: The analysis included 99 adult patients (avalglucosidase alfa n = 50; alglucosidase alfa n = 49). Patients who received avalglucosidase alfa had significantly greater odds of achieving a meaningful change versus alglucosidase alfa for the PDSS Shortness of Breath (OR [95% CI] 11.79 [2.24; 62.18]), Fatigue/Pain (6.24 [1.20; 32.54]), Morning Headache (13.98 [1.71; 114.18]), and Overall Fatigue (5.88 [1.37; 25.11]) domains, and were significantly more likely to meet meaningful change thresholds across multiple PDSS domains (all nominal p < 0.05). A numerically greater proportion of patients in the avalglucosidase alfa group were able to complete selected activities of the R-PAct compared with the alglucosidase alfa group. Significantly greater proportions of patients who received avalglucosidase alfa achieved meaningful improvements for EQ-5D-5L usual activities dimension, EQ visual analog scale, and all four PGIC domains. The proportion of patients with improvements in SF-12 PCS and MCS was greater in the avalglucosidase alfa group versus alglucosidase alfa group, but was not significant (p > 0.05). CONCLUSIONS: These analyses show that avalglucosidase alfa improves multiple symptoms and aspects of daily functioning, including breathing and mobility. This supports the clinical relevance of the effects of avalglucosidase alfa on HRQoL for patients with LOPD.

A strategic neurological research agenda for Europe: Towards clinically relevant and patient-centred neurological research priorities.

BACKGROUND AND PURPOSE: Neurological disorders constitute a significant portion of the global disease burden, affecting >30% of the world's population. This prevalence poses a substantial threat to global health in the foreseeable future. A lack of awareness regarding this high burden of neurological diseases has led to their underrecognition, underappreciation, and insufficient funding. Establishing a strategic and comprehensive research agenda for brain-related studies is a crucial step towards aligning research objectives among all pertinent stakeholders and fostering greater societal awareness. METHODS: A scoping literature review was undertaken by a working group from the European Academy of Neurology (EAN) to identify any existing research agendas relevant to neurology. Additionally, a specialized survey was conducted among all EAN scientific panels, including neurologists and patients, inquiring about their perspectives on the current research priorities and gaps in neurology. RESULTS: The review revealed the absence of a unified, overarching brain research agenda. Existing research agendas predominantly focus on specialized topics within neurology, resulting in an imbalance in the number of agendas across subspecialties. The survey indicated a prioritization of neurological disorders and research gaps. CONCLUSIONS: Building upon the findings from the review and survey, key components for a strategic and comprehensive neurological research agenda in Europe were delineated. This research agenda serves as a valuable prioritization tool for neuroscientific researchers, as well as for clinicians, donors, and funding agencies in the field of neurology. It offers essential guidance for creating a roadmap for research and clinical advancement, ultimately leading to heightened awareness and reduced burden of neurological disorders.

Which ultrasound-guided parasternal intercostal nerve block for post-sternotomy pain? Results from a prospective observational study.

BACKGROUND: Parasternal intercostal blocks (PSB) have been proposed for postoperative analgesia in patients undergoing median sternotomy. PSB can be achieved using two different approaches, the superficial parasternal intercostal plane block (SPIP) and deep parasternal intercostal plane block (DPIP) respectively. METHODS: We designed the present prospective, observational cohort study to compare the analgesic efficacy of the two approaches. Cardiac surgical patients who underwent full sternotomy from January to September 2022 were enrolled and divided into three groups, according to pain control strategy: morphine, SPIP, and DPIP group. Primary outcomes were was postoperative pain evaluated as absolute value of NRS at 12 h. Secondary outcomes were the NRS at 24 and 48 h, the need for salvage analgesia (both opioids and NSAIDs), incidence of postoperative nausea and vomiting, time to extubation, mechanical ventilation duration, and bowel disfunction. RESULTS: Ninety-six were enrolled. There was no significant difference in terms of median Numeric Pain Rating Scale at 24 h and at 48 h between the study groups. Total postoperative morphine consumption was 1.00 (0.00-3.00), 2.00 (0.00-5.50), and 15.60 mg (9.60-30.00) in the SPIP, DPIP, and morphine group, respectively (SPIP and DPIP vs morphine: p < 0.001). Metoclopramide consumption was lower in SPIP and DPIP group compared with morphine group (p = 0.01). There was no difference in terms of duration of mechanical ventilation and of bowel activity between the study groups. Two pneumothorax occurred in the DPIP group. CONCLUSIONS: Both SPIP and DPIP seem able to guarantee an effective pain management in the postoperative phase of cardiac surgeries via full median sternotomy while ensuring a reduced consumption of opioids and antiemetic drugs.

Safety outcomes and patients' preferences for home-based intravenous enzyme replacement therapy (ERT) in pompe disease and mucopolysaccharidosis type I (MPS I) disorder: COVID-19 and beyond.

BACKGROUND: The Italian Medicines Agency (AIFA) demands precise information on benefit/risk profile of home-based enzyme replacement therapy (ERT) for the treatment of patients with Pompe disease and Mucopolysaccharidosis type I (MPS I). This passage is necessary to obtain the authorization for ERT home therapy, even after the coronavirus disease-19 (COVID-19) pandemic period. This research intends to evaluate the safety, treatment satisfaction, and compliance of MPS I patients treated with laronidase (Aldurazyme®) and Pompe Disease patients treated with alglucosidase alfa (Myozyme®) in a homecare setting. RESULTS: We report herein an early interim analysis of the HomERT (Home infusions of ERT) study, a multicenter, non-interventional, double-cohort study that retrospectively analyzed 38 patients from 14 sites in Italy: cohort A (Pompe disease - 32 patients) and cohort B (MPS I - 6 patients). Among the selected patients who started home therapy before enrollment, the average number of missed home-based infusions was 0.7 (1.3) in cohort A and 3.8 (6.4) in cohort B with no return to the hospital setting. Irrespective of the treatment location, 3 prior ADRs per cohort were reported. The majority of patients preferred home-based infusions (cohort A: 96.9%; cohort B: 100%): the main reason was attributed to treatment convenience (cohort A: 81.3%; cohort B: 83.3%). Despite the underlying conditions, most patients self-evaluated their health as "good" (cohort A: 50%; cohort B: 83.3%). CONCLUSIONS: Evidence of favorable safety profile, improved treatment compliance and personal satisfaction validates the use of ERT with laronidase and alglucosidase alfa as a strong candidate for home therapy.

Factors associated with hemorrhagic transformation after endovascular treatment despite early recanalization.

PURPOSE: To identify new factors associated with hemorrhagic transformation (HT) despite early recanalization in patients with acute ischemic stroke treated with mechanical thrombectomy. METHODS: We retrospectively included patients with known onset of large vessel occlusion treated with mechanical thrombectomy +/- intravenous thrombolysis. Non-contrast CT was performed at 24 +/- 12 h from endovascular procedure. We collected data on patient characteristics, risk factors, radiological and treatment features, stroke severity on admission and discharge, carotid intima-media thickness (CIMT), Neutrophils-to-Lymphocytes ratio (NLR), white matter hyperintensities measured according to the Fazekas score on FLAIR MRI data. The main outcome measures were the incidence of HT and factors associated with it. Secondary outcome measures were symptomatic intracerebral hemorrhage and parenchymal hematoma. RESULTS: Of 874 patients, 472 met the inclusion criteria, 211 (44.7%) had HT. Factors significantly associated with increased risk of HT included onset-to-recanalization time, CIMT (normal/mild), ASPECT-MRI < 6, and a higher NLR. We found that beyond 7.67 h from onset-to-recanalization, the risk of HT increases and exceeds 50%. ASPECT-MRI, NLR, and CIMT independently predict HT despite early recanalization. CONCLUSIONS: We identified novel factors associated with HT in patients with acute ischemic stroke of known onset treated with mechanical thrombectomy. We found that at 7.67 h from onset to recanalization, the risk of HT is >50%, and we identified factors responsible for HT despite early recanalization.

Erector spinae plane block versus paravertebral block for postoperative pain management in thoracic surgery: a systematic review and meta-analysis.

INTRODUCTION: The 2018 guidelines for enhanced recovery in thoracic surgery recommend paravertebral block (PVB) for postoperative pain management. However, recent studies demonstrate that erector spinae plane block (ESPB) achieves similar postoperative pain control with reduced block-related complications. EVIDENCE ACQUISITION: We conducted a meta-analysis of randomized controlled trials to evaluate the analgesic efficacy and safety of ESPB versus PVB for pain management after thoracic surgery. PubMed, Embase, and Scopus were searched through December 2022 (PROSPERO registration - CRD42023395593). Primary outcomes were postoperative pain scores, resting at 6, 12, 24, and 48 hours, and at movement at 24 and 48 hours. Secondary outcomes included opioid consumption at 24 and 48 hours, and incidence of postoperative nausea and vomiting or block-related complications in the first 48 hours. EVIDENCE SYNTHESIS: Ten randomized control trials enrolling a total of 624 total patients were included. There were no significant differences in pain scores, resting or at movement, at any time points except reduced resting pain scores at 12 hours with PVB (mean difference [MD]) 0.60, 95% confidence interval [CI] 0.32 to 0.88). Opioid consumption demonstrated no significant differences at 24 hours; PVB reduced opioid consumption at 48 hours (MD 0.40, 95% CI -0.09 to 0.89). There were no significant differences in postoperative nausea or vomiting. ESPB exhibited a nonsignificant trend toward reduced cumulative block-related complications (risk difference [RD] 0.05, 95% CI -0.10 to 0.00). CONCLUSIONS: Compared with PVB, ESPB is safe and demonstrates no clinically significant differences in pain management after thoracic surgery.

The safety of thoracic paravertebral block and erector spinae plane block in patients treated with anticoagulant or antiplatelet therapy. A narrative review of the evidence.

INTRODUCTION: The management of thoracic paravertebral block (TPVB) and erector spine plane block (ESPB) in patients treated with anticoagulant or antiplatelet therapy is based on limited clinical data, mostly from single case reports. Scientific societies and organizations do not provide strong detailed indications about the limitations of these regional anesthesia techniques in patients receiving antithrombotic therapy. This review summarizes evidence regarding TPVB and ESPB in patients under antithrombotic therapy. EVIDENCE ACQUSITION: A literature review from PubMed/MEDLINE, EMBASE, Cochrane, Google Scholar and Web of Science databases was conducted from 1999 to 2022 to identify articles concerning TPVB and ESPB for cardio-thoracic surgery or thoracic procedures in patients under anticoagulant or antiplatelet therapy. EVIDENCE SYNTHESIS: A total of 1704 articles were identified from the initial search. After removing duplicates and not-pertinent articles, 15 articles were analyzed. The results demonstrated a low risk of bleeding for TPVB and minimal or absent risk for ESPB. Ultrasound guidance was extensively used to perform ESPB, but not for TPVB. CONCLUSIONS: Although the low level of evidence available, TPVB and ESPB are reasonably safe options in patients ineligible for epidural anesthesia due to antithrombotic therapy. The few published studies suggest that ESPB offers a risk profile safer than TPVB and the use of ultrasound guidance minimizes any complication. Since the literature available does not allow us to draw definitive conclusions, future adequately-powered trials are warranted to determine the indications and the safety of TPVB and ESPB in patients receiving anticoagulant or antiplatelet therapy.

Data from the European registry for patients with McArdle disease (EUROMAC): functional status and social participation.

BACKGROUND: The European registry for individuals with GSD5 and other muscle glycogenosis (EUROMAC) was launched to register rare muscle glycogenosis in Europe, to facilitate recruitment for research trials and to learn about the phenotypes and disseminate knowledge about the diseases. A network of twenty collaborating partners from eight European countries and the US contributed data on rare muscle glycogenosis in the EUROMAC registry. METHODS: Following the initial report on demographics, neuromuscular features and comorbidity (2020), we here present the data on social participation, previous and current treatments (medication, supplements, diet and rehabilitation) and limitations. Furthermore, the following questionnaires were used: Fatigue severity scale (FSS), WHO Disability Assessment Scale (DAS 2.0), health related quality of life (SF36) and International Physical Activity Questionnaire (IPAQ). RESULTS: Of 282 participants with confirmed diagnoses of muscle glycogenosis, 269 had GSD5. Of them 196 (73%) completed all questionnaires; for the others, the data were incomplete. The majority, 180 (67%) were currently working. Previous medical treatments included pain medication (23%) and rehabilitation treatment (60%). The carbohydrate-rich diet was reported to be beneficial for 68%, the low sucrose diet for 76% and the ketogenic diet for 88%. Almost all participants (93%) reported difficulties climbing stairs. The median FSS score was 5.22, indicating severe fatigue. The data from the WHODAS and IPAQ was not of sufficient quality to be interpreted. CONCLUSIONS: The EUROMAC registry have provided insight into the functional and social status of participants with GSD5: most participants are socially active despite limitations in physical and daily life activities. Regular physical activity and different dietary approaches may alleviate fatigue and pain.

Digital health and Clinical Patient Management System (CPMS) platform utility for data sharing of neuromuscular patients: the Italian EURO-NMD experience.

BACKGROUND: The development of e-health technologies for teleconsultation and exchange of knowledge is one of the core purposes of European Reference Networks (ERNs), including the ERN EURO-NMD for rare neuromuscular diseases. Within ERNs, the Clinical Patient Management System (CPMS) is a web-based platform that seeks to boost active collaboration within and across the network, implementing data sharing. Through CPMS, it is possible to both discuss patient cases and to make patients' data available for registries and databases in a secure way. In this view, CPMS may be considered a sort of a temporary storage for patients' data and an effective tool for data sharing; it facilitates specialists' consultation since rare diseases (RDs) require multidisciplinary skills, specific, and outstanding clinical experience. Following European Union (EU) recommendation, and to promote the use of CPMS platform among EURO-NMD members, a twelve-month pilot project was set up to train the 15 Italian Health Care Providers (HCPs). In this paper, we report the structure, methods, and results of the teaching course, showing that tailored, ERN-oriented, training can significantly enhance the profitable use of the CPMS. RESULTS: Throughout the training course, 45 professionals learned how to use the many features of the CPMS, eventually opening 98 panels of discussion-amounting to 82% of the total panels included in the EURO-NMD. Since clinical, genetic, diagnostic, and therapeutic data of patients can be securely stored within the platform, we also highlight the importance of this platform as an effective tool to discuss and share clinical cases, in order to ease both case solving and data storing. CONCLUSIONS: In this paper, we discuss how similar course could help implementing the use of the platform, highlighting strengths and weaknesses of e-health for ERNs. The expected result is the creation of a "map" of neuromuscular patients across Europe that might be improved by a wider use of CPMS.

Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial.

BACKGROUND AND OBJECTIVES: Primary mitochondrial myopathies (PMMs) encompass a group of genetic disorders that impair mitochondrial oxidative phosphorylation, adversely affecting physical function, exercise capacity, and quality of life (QoL). Current PMM standards of care address symptoms, with limited clinical impact, constituting a significant therapeutic unmet need. We present data from MMPOWER-3, a pivotal, phase-3, randomized, double-blind, placebo-controlled clinical trial that evaluated the efficacy and safety of elamipretide in participants with genetically confirmed PMM. METHODS: After screening, eligible participants were randomized 1:1 to receive either 24 weeks of elamipretide at a dose of 40 mg/d or placebo subcutaneously. Primary efficacy endpoints included change from baseline to week 24 on the distance walked on the 6-minute walk test (6MWT) and total fatigue on the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA). Secondary endpoints included most bothersome symptom score on the PMMSA, NeuroQoL Fatigue Short-Form scores, and the patient global impression and clinician global impression of PMM symptoms. RESULTS: Participants (N = 218) were randomized (n = 109 elamipretide; n = 109 placebo). The m0ean age was 45.6 years (64% women; 94% White). Most of the participants (n = 162 [74%]) had mitochondrial DNA (mtDNA) alteration, with the remainder having nuclear DNA (nDNA) defects. At screening, the most frequent bothersome PMM symptom on the PMMSA was tiredness during activities (28.9%). At baseline, the mean distance walked on the 6MWT was 336.7 ± 81.2 meters, the mean score for total fatigue on the PMMSA was 10.6 ± 2.5, and the mean T score for the Neuro-QoL Fatigue Short-Form was 54.7 ± 7.5. The study did not meet its primary endpoints assessing changes in the 6MWT and PMMSA total fatigue score (TFS). Between the participants receiving elamipretide and those receiving placebo, the difference in the least squares mean (SE) from baseline to week 24 on distance walked on the 6MWT was -3.2 (95% CI -18.7 to 12.3; p = 0.69) meters, and on the PMMSA, the total fatigue score was -0.07 (95% CI -0.10 to 0.26; p = 0.37). Elamipretide treatment was well-tolerated with most adverse events being mild to moderate in severity. DISCUSSION: Subcutaneous elamipretide treatment did not improve outcomes in the 6MWT and PMMSA TFS in patients with PMM. However, this phase-3 study demonstrated that subcutaneous elamipretide is well-tolerated. TRIAL REGISTRATION INFORMATION: Trial registered with clinicaltrials.gov, Clinical Trials Identifier: NCT03323749; submitted on October 12, 2017; first patient enrolled October 9, 2017. CLINICALTRIALS: gov/ct2/show/NCT03323749?term = elamipretide&draw = 2&rank = 9. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that elamipretide does not improve the 6MWT or fatigue at 24 weeks compared with placebo in patients with primary mitochondrial myopathy.