Long-Term Effectiveness of Galcanezumab in the Prevention of Migraine: An Italian Retrospective Analysis (REALITY).

BACKGROUND: Galcanezumab is approved in the European Union (EU) as migraine prophylaxis in adults with at least four migraine days per month. The aim of this retrospective observational study was to evaluate the long-term effectiveness of galcanezumab on migraine-related burdens and its impact on the use of healthcare resources for migraine prophylaxis in an Italian setting. METHODS: This retrospective study was conducted in patients with migraine who initiated treatment with galcanezumab for migraine prevention between September 2019 and December 2020. Patient data for monthly migraine days (MMDs) and MMDs with acute medication intake were obtained by medical chart reviews. Information on patient-reported outcomes (using the Migraine Disability Assessment [MIDAS] questionnaire and Headache Impact Test 6 [HIT-6] questionnaire) and on the use of healthcare resources were also collected. The time points of interest were 1, 3, 6, 9, 12 months after the initiation of galcanezumab, and the most recent time point available during follow-up. RESULTS: A total of 207 patients were enrolled in the study. Starting from month 3 after treatment initiation, more than half of the patients presented at least a 50% reduction in MMDs, and approximately one-third of non-responders at month 3 became responders at month 6. From month 3 to month 12, MMDs decreased on average by 10 days. Headache impact and disability, as well as migraine-associated health resource utilization decreased significantly during the treatment period. A positive significant association among the three dimensions of clinical burden (MMDs, MIDAS and days of acute medication intake) was also observed. CONCLUSION: The results of this Italian real-world study confirmed that galcanezumab has a rapid onset of effect and provides a long-term response among patients over different migraine-related burdens. The use of healthcare resources was also remarkably reduced.

Visual migraine aura iconography: A multicentre, cross-sectional study of individuals with migraine with aura.

INTRODUCTION: Visual disturbances are the most common symptoms of migraine aura. These symptoms can be described systematically by subdividing them into elementary visual symptoms. Since visual symptoms of migraine aura are not easy to describe verbally, we developed a collection of images illustrating previously reported elementary visual symptoms. OBJECTIVES: To test a standardised visual migraine aura iconography in a large population of migraine with aura patients and to improve it based on the participants' feedback. METHODS: We created a set of images representing 25 elementary visual symptoms and a web-based survey where participants could report whether they recognised these images as part of their visual aura. Elementary visual symptoms could also be recognised via a corresponding text description or described in a free text by participants. Individuals with migraine aura recruited from four tertiary headache centres (in Switzerland, Denmark, Norway and Italy) were invited to complete the survey. RESULTS: Two hundred and fifteen participants completed the study (78.9% women, median age 36). They recognised a total of 1645 elementary visual symptoms from our predefined list. Of those, 1291 (78.4%) where recognised via standardised iconography images. A new type of elementary visual symptom was reported by one participant. CONCLUSION: Most elementary visual symptoms experienced by participants were recognised via the standardised iconography. This tool can be useful for clinical as well as research purposes.

What has neurophysiology revealed about migraine and chronic migraine?

Since the first electroencephalographic recordings obtained by Golla and Winter in 1959, researchers have used a variety of neurophysiological techniques to determine the mechanisms underlying recurrent migraine attacks. Neurophysiological methods have shown that the brain during the interictal phase of an episodic migraine is characterized by a general hyperresponsiveness to sensory stimuli, a malfunction of the monoaminergic brainstem circuits, and by functional alterations of the thalamus and thalamocortical loop. All of these alterations vary plastically during the phases of the migraine cycle and interictally with the days following the attack. Both episodic migraineurs recorded during an attack and chronic migraineurs are characterized by a general increase in the cortical amplitude response to peripheral sensory stimuli; this is an electrophysiological hallmark of a central sensitization process that is further reinforced through medication overuse. Considering the large-scale functional involvement and the main roles played by the brainstem-thalamo-cortical network in selection, elaboration, and learning of relevant sensory information, future research should move from searching for one specific primary site of dysfunction at the macroscopic level, to the chronic, probably genetically determined, molecular dysfunctions at the synaptic level, responsible for short- and long-term learning mechanisms.

Development and validation of a new standardized measure for assessing experiences of discrimination within mental health services. A participatory research project.

AIMS: People with mental disorders frequently report experiences of discrimination within mental health services, which can have significant detrimental effects on individuals' well-being and recovery. This study aimed to develop and validate a new standardized measure aiming to assess experiences of stigmatization among people with mental disorders within mental health services. METHODS: The scale was developed in Italian and tested for ease of use, comprehension, acceptability, relevance of items and response options within focus group session. A cross-sectional validation survey was conducted among mental health service users in Italy. Exploratory factor analysis with Promax oblique rotation, the Kaiser-Meyer-Olkin (KMO) measure of sampling adequacy and the Bartlett's test of sphericity were used to assess the suitability of the sample for factor analysis. Reliability was assessed as internal consistency using Cronbach's alpha and as test-retest reliability using weighted kappa and intraclass correlation coefficient (ICC). Precision was examined by Kendall's tau-b coefficient. RESULTS: Overall, 240 people with mental disorders participated in the study; 56 also completed the retest evaluation after 2 weeks. The 18 items of the scale converged over a two-factor solution ('Dignity violation and personhood devaluation' and 'Perceived life restrictions and social exclusion'), accounting for 56.4% of the variance (KMO 0.903; Bartlett's test p < 0.001). Cronbach's alpha for the total score was 0.934. The scale showed one item with kappa above 0.81, four items between 0.61 and 0.80, ten items between 0.41 and 0.60, two items between 0.21 and 0.40 and only one item below 0.20. ICC was 0.928 (95% CI 0.877-0.958). Kendall's tau-b ranged from 0.450 to 0.617 (p < 0.001). CONCLUSIONS: The newly developed scale represents a valid and reliable measure for assessing experiences of stigma among patients receiving care within mental health services. The scale has provided initial evidence of being specifically tailored for individuals with psychotic and bipolar disorders. However, the factorial structure of the scale should be replicated through a confirmatory factor analysis on a larger sample of individuals with these conditions.

The positive impact on translational research of Fondazione italiana di ricerca per la Sclerosi Laterale Amiotrofica (AriSLA), a non-profit foundation focused on amyotrophic lateral sclerosis. Convergence of ex-ante evaluation and ex-post outcomes when goals are set upfront.

Charities investing on rare disease research greatly contribute to generate ground-breaking knowledge with the clear goal of finding a cure for their condition of interest. Although the amount of their investments may be relatively small compared to major funders, the advocacy groups' clear mission promotes innovative research and aggregates highly motivated and mission-oriented scientists. Here, we illustrate the case of Fondazione italiana di ricerca per la Sclerosi Laterale Amiotrofica (AriSLA), the main Italian funding agency entirely dedicated to amyotrophic lateral sclerosis research. An international benchmark analysis of publications derived from AriSLA-funded projects indicated that their mean relative citation ratio values (iCite dashboard, National Institutes of Health, U.S.) were very high, suggesting a strong influence on the referring international scientific community. An interesting trend of research toward translation based on the "triangle of biomedicine" and paper citations (iCite) was also observed. Qualitative analysis on researchers' accomplishments was convergent with the bibliometric data, indicating a high level of performance of several working groups, lines of research that speak of progression toward clinical translation, and one study that has progressed from the investigation of cellular mechanisms to a Phase 2 international clinical trial. The key elements of the success of the AriSLA investment lie in: (i) the clear definition of the objectives (research with potential impact on patients, no matter how far), (ii) a rigorous peer-review process entrusted to an international panel of experts, (iii) diversification of the portfolio with ad hoc selection criteria, which also contributed to bringing new experts and younger scientists to the field, and (iv) a close interaction of AriSLA stakeholders with scientists, who developed a strong sense of belonging. Periodic review of the portfolio of investments is a vital practice for funding agencies. Sharing information between funding agencies about their own policies and research assessment methods and outcomes help guide the international debate on funding strategies and research directions to be undertaken, particularly in the field of rare diseases, where synergy is a relevant enabling factor.

Harassment in the headache field: a global web-based cross-sectional survey.

BACKGROUND: Matters of workplace harassment are an important issue. This issue needs to be recognized and studied to prevent occurrences. These important sensitive areas of effective workplace management are increasingly gaining more interest. We aimed to identify the prevalence of workplace sexual, verbal and physical harassment among headache professionals. METHODS: We adopted a cross­sectional exploratory survey approach with quantitative design. The survey was distributed electronically among headache healthcare and research professionals globally through the International Headache Society (IHS). RESULTS: Data were obtained from 579 respondents (55.3%; 320/579 women). A large percentage of respondents (46.6%; 270/579) had experienced harassment; specifically, 16.1% (93/578) reported sexual harassment, 40.4% (234/579) verbal harassment and 5.5% (32/579) physical harassment. Women were almost seven times more likely to experience sexual harassment compared to men (odds ratio = 6.8; 95% confidence interval = 3.5-13.2). Although women did also more frequently report other types of harassment, this was not statistically significant (odds ratio = 1.4; 95% confidence interval = 1.0-2.0). CONCLUSIONS: Lifetime exposure to workplace harassment is prevalent among headache professionals, especially in women. The present study uncovers a widespread issue and calls for strategies to be implemented for building a healthy and safe workplace environment.

Perceived barriers to career progression in the headache field: A global web-based cross-sectional survey.

BACKGROUND: It is well recognized that underrepresented and minoritized groups do not have the same career opportunities. However, there are limited data on the range and specifics of potential barriers that withhold people in headache medicine and science from reaching their full potential. Moreover, people from different geographical regions often perceive different challenges. We aimed to identify world-wide perceived career barriers and possibilities for promoting equality amongst professionals in the headache fields. METHODS: A cross-sectional online survey was conducted among professionals in the field of headache globally. The questions of the survey were aimed at assessing perceived career barriers in four domains: professional recognition, opportunities in scientific societies, clinical practice, and salary and compensation. Perceived mentorship was also assessed. RESULTS: In total 580 responders completed the survey (55.3% women). Gender was the most important perceived barrier in almost all domains. Additionally, country of birth emerged as an important barrier to participation in international scientific societies. Career barriers varied across world regions. CONCLUSION: It is essential that longstanding and ongoing disparities by gender and country of origin for professionals in the headache field are globally acknowledged and addressed in areas of recruitment, retention, opportunities, mentor- and sponsorships, and advancement.

Preventive pharmacological treatment in subjects at risk for fatal familial insomnia: science and public engagement.

Engaging patients as partners in biomedical research has gradually gained consensus over the last two decades. They provide a different perspective on health priorities and help to improve design and outcomes of clinical studies. This paper describes the relationship established between scientists and members of a large family at genetic risk of very rare lethal disease, fatal familial insomnia (FFI). This interaction led to a clinical trial based on the repurposing of doxycycline - an antibiotic with a known safety profile and optimal blood-brain barrier passage - which in numerous preclinical and clinical studies had given evidence of its potential therapeutic effect in neurodegenerative disorders, including prion diseases like FFI. The design of this trial posed several challenges, which were addressed jointly by the scientists and the FFI family. Potential participants excluded the possibility of being informed of their own FFI genotype; thus, the trial design had to include both carriers of the FFI mutation (10 subjects), and non-carriers (15 subjects), who were given placebo. Periodic clinical controls were performed on both groups by blinded examiners. The lack of surrogate outcome measures of treatment efficacy has required to compare the incidence of the disease in the treated group with a historical dataset during 10 years of observation. The trial is expected to end in 2023. Regardless of the clinical outcome, it will provide worthwhile knowledge on the disease. It also offers an important example of public engagement and collaboration to improve the quality of clinical science.

Changes in acute headache medication use and health care resource utilization: Results from a randomized, double-blind, placebo-controlled clinical trial evaluating galcanezumab in adults with treatment-resistant migraine (CONQUER).

BACKGROUND: Patients with migraine, particularly with multiple prior preventive treatment failures, often have high rates of acute headache medication use and are at risk for overuse (acute or symptomatic headache medication use between 10 and 15 days per month [depending on the medication] for > 3 months). Furthermore, these patients have greater health care resource utilization (HCRU). OBJECTIVE: To examine acute headache medication use and HCRU with galcanezumab compared with placebo in a population with multiple prior migraine preventive treatment failures. METHODS: In the 3-month double-blind phase, patients with episodic or chronic migraine and treatment failures to 2 to 4 standard-of-care migraine preventive categories (lack of effectiveness or safety/tolerability) received galcanezumab 120 mg/month (following a 240-mg loading dose) or placebo; an optional 3 month open-label phase followed. Acute headache medication use (monthly days with acute headache medication utilization) was self-reported daily. The change from baseline in monthly days with acute headache medication used a mixed-model repeated measures analysis. HCRU was reported at baseline (for the previous 6 months) and at monthly visits. Migraine-related HCRU rates were evaluated in the total population per 100 patient-years. RESULTS: Of the 462 patients (galcanezumab n=232, placebo n=230), baseline mean days/month of acute headache medication was 12.3; 44.8% had acute headache medication overuse. Across months 1-3, least squares (LS) mean reductions in acute headache medication use were greater for the galcanezumab group (4.2) compared with placebo (0.9); the LS mean difference was 3.4 (95% CI = 2.7-4.1; P < 0.0001). Greater reductions in the galcanezumab group were observed as early as month 1; statistical separation continued at months 2 and 3 (all P < 0.0001). During the open-label phase, reductions from baseline ranged from 4.7 to 5.3 days and were similar in patients who transitioned from placebo to patients continuing galcanezumab. Reductions from baseline of migraine-specific health care visits (double-blind phase) were numerically greater with galcanezumab than placebo (215.5 vs 155.3). Patients switching to galcanezumab had reductions (212.9 days) similar to patients continuing galcanezumab (222.6 days). Migraine-specific emergency department visits decreased by two-thirds at month 3 in the galcanezumab group compared with nearly no reduction in the placebo group that experienced a similar reduction during the open-label phase. For both groups, migraine-specific hospitalizations were less than 2 per 100 patient-years. CONCLUSIONS: These results demonstrate that galcanezumab has the potential to reduce acute headache medication use and overuse and HCRU in patients with prior migraine preventive treatment failures. DISCLOSURES: Data were presented in part as a poster presentation at the 14th European Headache Congress (European Headache Federation), Virtual Meeting, July 3-5, 2020. Dr Ambrosini is on the advisory board for Eli Lilly and Company and received honorarium from Teva, Novartis, and Eli Lilly and Company. Dr Estemalik is on the advisory boards for Eli Lilly and Company, Lundbeck, and Allergan and the speakers' bureau for Teva, Lundbeck, Eli Lilly and Company, Allergan, and Biohaven. He received consulting fees from Eli Lilly and Company, Teva, Lundbeck, and Allergan and support for attending meetings and/or travel from Eli Lilly and Company, Allergan, Biohaven, Teva, and Lundbeck. Dr Pascual received research support from Instituto de Salud Carlos III, Ministry of Economy, Spain. He was also on advisory boards for Allergan, Amgen-Novartis, Eli Lilly and Company, and Stendhal and received consulting fees or honoraria from Allegan, Eli Lilly and Company, Novartis-Amgen, and Teva. Dr Rettiganti is an employee of Eli Lilly and Company and/or one of its subsidiaries, Indianapolis, IN. She is also a minor stock and restricted stockholder of Eli Lilly and Company. Mr. Stroud and Ms. Day are employees of Eli Lilly and Company and/or one of its subsidiaries, Indianapolis, IN. Dr Ford is an employee of and holds stock of Eli Lilly and Company and/or one of its subsidiaries, Indianapolis, IN. She also received support for attending meetings and/or travel from Eli Lilly and Company.

Fondazione Telethon and Unione Italiana Lotta alla Distrofia Muscolare, a successful partnership for neuromuscular healthcare research of value for patients.

In 2001, Fondazione Telethon and the Italian muscular dystrophy patient organisation Unione Italiana Lotta alla Distrofia Muscolare joined their efforts to design and launch a call for grant applications specifically dedicated to clinical projects in the field of neuromuscular disorders. This strategic initiative, run regularly over the years and still ongoing, aims at supporting research with impact on the daily life of people with a neuromuscular condition and is centred on macro-priorities identified by the patient organisation. It is investigator-driven, and all proposals are peer-reviewed for quality and feasibility. Over the years, this funding program contributed to strengthening the activities of the Italian neuromuscular clinical network, reaching many achievements in healthcare research. Moreover, it has been an enabling factor for innovative therapy experimentation at international level and prepared the clinical ground to make therapies available to Italian patients. The ultimate scope of healthcare research is to ameliorate the delivery of care. In this paper, the achievements of the funded studies are analysed also from this viewpoint, to ascertain to which extent they have fulfilled the original goals established by the patient organisation. The evidence presented indicates that this has been a highly fruitful program. Factors that contributed to its success, lessons learned, challenges, and issues that remain to be addressed are discussed to provide practical examples of an experience that could inspire also other organizations active in the field of rare disease research.

Update on noninvasive neuromodulation for migraine treatment-Vagus nerve stimulation.

Noninvasive neurostimulation methods are particularly suited for migraine treatment thanks to their most favorable adverse event profile. Among them, noninvasive vagus nerve stimulation (nVNS) has raised great hope because of the role the vagus nerve is known to play in pain modulation, inflammation and brain excitability. We will critically review the clinical studies performed for migraine attack treatment and migraine prevention with the GammaCore® device, which allows cervical vagus nerve stimulation. nVNS is effective for the abortive treatment of migraine attacks, although the effect size is modest and numbers-to-treat appear not superior to those of other noninvasive neurostimulation methods, and inferior to those of oral triptans. The effect of nVNS with the GammaCore® in migraine prevention is not superior to sham stimulation, except possibly in patients with high adherence to the treatment. Both in acute and preventive trials, nVNS was characterized by an outstanding tolerance and safety profile, like the other noninvasive neurostimulation techniques. In physiological animal and human studies, cervical nVNS was shown to generate somatosensory evoked responses, to modulate pain perception and several areas of the cerebral pain network, and to inhibit experimental cortical spreading depression, which are relevant effects for migraine therapy.

"Be an ambassador for change that you would like to see": a call to action to all stakeholders for co-creation in healthcare and medical research to improve quality of life of people with a neuromuscular disease.

BACKGROUND: Patient and public involvement for co-creation is increasingly recognized as a valuable strategy to develop healthcare research targeting patients' real needs. However, its practical implementation is not as advanced and unanimously accepted as it could be, due to cultural differences and complexities of managing healthcare programs and clinical studies, especially in the rare disease field. MAIN BODY: The European Neuromuscular Centre, a European foundation of patient organizations, involved its key stakeholders in a special workshop to investigate the position of the neuromuscular patient community with respect to healthcare and medical research to identify and address gaps and bottlenecks. The workshop took place in Milan (Italy) on January 19-20, 2018, involving 45 participants who were mainly representatives of the patient community, but also included experts from clinical centers, industry and regulatory bodies. In order to provide practical examples and constructive suggestions, specific topics were identified upfront. The first set of issues concerned the quality of life at specific phases of a patient's life, such as at the time of diagnosis or during pediatric to adult transition, and patient involvement in medical research on activities in daily living including patient reported outcome measures. The second set of issues concerned the involvement of patients in the management of clinical research tools, such as registries and biobanks, and their participation in study design or marketing authorization processes. Introductory presentations were followed by parallel working group sessions, to gain constructive contributions from all participants. The concept of shared decision making was used to ensure, in discussions, a partnership-based identification of the wishes and needs of all stakeholders involved, and the "ladder of participation" tool served as a model to evaluate the actual and the desired level of patients' involvement in all topics addressed. A general consensus on the outcome of the meeting was collected during the final plenary session. This paper reports the outcome of the workshop and the specific suggestions derived from the analysis of the first set of topics, related to quality of life. The outcomes of the second set of topics are reported elsewhere and are only briefly summarized herein for the sake of completeness. CONCLUSIONS: The neuromuscular community proved to be very active and engaged at different levels in the healthcare initiatives of interest. The workshop participants critically discussed several topics, providing practical examples where different stakeholders could play a role in making a change and bridging gaps. Overall, they indicated the need for education of all stakeholders for better communication, where everyone should become an ambassador to promote real change. Support should also come from institutions and healthcare bodies both at structural and economic level.

Withdrawal from acute medication normalises short-term cortical synaptic potentiation in medication overuse headache.

OBJECTIVES: To study the effects of a standard acute medication withdrawal program on short-term cortical plasticity mechanisms in patients with medication overuse headache (MOH). METHODS: Thirteen patients with MOH and 16 healthy volunteers underwent repetitive transcranial magnetic stimulation (rTMS) over the left motor cortex; in patients with MOH, recordings were performed before and after a 3-week medication withdrawal program. Ten trains of 10 stimuli each (120% resting motor threshold) were delivered at 1 Hz or 5 Hz in two separate sessions in a randomised order. Motor evoked potential (MEP) amplitudes were measured from the right first dorsal interosseous muscle and the slope of the linear regression line from the first to the tenth stimuli was calculated for each participant. RESULTS: All subjects exhibited MEP amplitude inhibition in response to 1 Hz rTMS. Alternatively, the 5-Hz trains of rTMS inhibited rather than potentiated MEP amplitudes in patients with MOH. The physiological potentiating effect of 5 Hz rTMS on MEP amplitudes was restored after drug withdrawal and in proportion with the percentage reduction in monthly headache days in patients with MOH. CONCLUSIONS: The results suggest that acute medication withdrawal normalises brain responses in patients with MOH. Clinical improvements after medication withdrawal may reflect the reversal of neurophysiological dysfunction. Accordingly, medication withdrawal should be offered to patients with MOH as early as possible in order to prevent the development of more pronounced alterations in brain plasticity.

The Position of Neuromuscular Patients in Shared Decision Making. Report from the 235th ENMC Workshop: Milan, Italy, January 19-20, 2018.

In the era of patient-centered medicine, shared decision-making (SDM) - in which healthcare professionals and patients exchange information and preferences and jointly reach a decision - has emerged as the gold standard model for the provision of formal healthcare. Indeed, in many geographical settings, patients are frequently invited to participate in choices concerning the design and delivery of their medical management. From a clinical perspective, benefits of this type of patient involvement encompass, for example, enhanced treatment satisfaction, improved medical compliance, better health outcomes, and maintained or promoted quality of life. Yet, although the theory and enactment of SDM in healthcare are well-described in the literature [1-3], comparatively less attention has been devoted to contextualizing questions relating to if, when, and how to include patients in decisions within medical research. In this context, patient involvement would be expected to be potentially relevant for and applicable to a wide range of activities and processes, from the identification of research priorities and development of grant applications, to the design of patient information and consent procedures, formulation of interventions, identification and recruitment of study sample populations, feasibility of a clinical trial, identification, selection, and specification of endpoints and outcomes in clinical trials and observational studies, data collection and analysis, and dissemination of results. To this end, 45 clinicians, healthcare professionals, researchers, patients, caregivers, and representatives from regulatory authorities and pharmaceutical companies from 15 different countries met to discuss the level of involvement of patients with neuromuscular diseases, specifically in the following settings of medical research for neuromuscular diseases: i) registries and biobanks; ii) clinical trials; and iii) regulatory processes. In this report, we present summaries of the talks that were given during the workshop, as well as discussion outcomes from the three topic areas listed above.

Correction to: Practical and clinical utility of non-invasive vagus nerve stimulation (nVNS) for the acute treatment of migraine: a post hoc analysis of the randomized, sham-controlled, double-blind PRESTO trial.

Following publication of the original article [1], the authors notified us that a part of the Figure 3 legend was omitted during proofing stage.

Correction to: Consistent effects of non-invasive vagus nerve stimulation (nVNS) for the acute treatment of migraine: additional findings from the randomized, sham-controlled, double-blind PRESTO trial.

Following publication of the original article [1], the authors notified us o that the Table 1 citation within the legend was not presented as initially requested.

Consistent effects of non-invasive vagus nerve stimulation (nVNS) for the acute treatment of migraine: additional findings from the randomized, sham-controlled, double-blind PRESTO trial.

BACKGROUND: Non-invasive vagus nerve stimulation (nVNS) has been shown to be practical, safe, and well tolerated for treating primary headache disorders. The recent multicenter, randomized, double-blind, sham-controlled PRESTO trial provided Class I evidence that for patients with episodic migraine, nVNS significantly increases the probability of having mild pain or being pain-free 2 h post stimulation. We report additional pre-defined secondary and other end points from PRESTO that demonstrate the consistency and durability of nVNS efficacy across a broad range of outcomes. METHODS: After a 4-week observation period, 248 patients with episodic migraine with/without aura were randomly assigned to acute treatment of migraine attacks with nVNS (n = 122) or a sham device (n = 126) during a double-blind period lasting 4 weeks (or until the patient had treated 5 attacks). All patients received nVNS therapy during the subsequent 4-week/5-attack open-label period. RESULTS: The intent-to-treat population consisted of 243 patients. The nVNS group (n = 120) had a significantly greater percentage of attacks treated during the double-blind period that were pain-free at 60 (P = 0.005) and 120 min (P = 0.026) than the sham group (n = 123) did. Similar results were seen for attacks with pain relief at 60 (P = 0.025) and 120 min (P = 0.018). For the first attack and all attacks, the nVNS group had significantly greater decreases (vs sham) in pain score from baseline to 60 min (P = 0.029); the decrease was also significantly greater for nVNS at 120 min for the first attack (P = 0.011). Results during the open-label period were consistent with those of the nVNS group during the double-blind period. The incidence of adverse events (AEs) and adverse device effects was low across all study periods, and no serious AEs occurred. CONCLUSIONS: These results further demonstrate that nVNS is an effective and reliable acute treatment for multiple migraine attacks, which can be used safely while preserving the patient's option to use traditional acute medications as rescue therapy, possibly decreasing the risk of medication overuse. Together with its practicality and optimal tolerability profile, these findings suggest nVNS has value as a front-line option for acute treatment of migraine. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02686034 .

The Italian neuromuscular registry: a coordinated platform where patient organizations and clinicians collaborate for data collection and multiple usage.

BACKGROUND: The worldwide landscape of patient registries in the neuromuscular disease (NMD) field has significantly changed in the last 10 years, with the international TREAT-NMD network acting as strong driver. At the same time, the European Medicines Agency and the large federations of rare disease patient organizations (POs), such as EURORDIS, contributed to a great cultural change, by promoting a paradigm shift from product-registries to patient-centred registries. In Italy, several NMD POs and Fondazione Telethon undertook the development of a TREAT-NMD linked patient registry in 2009, with the referring clinical network providing input and support to this initiative through the years. This article describes the outcome of this joint effort and shares the experience gained. METHODS: The Italian NMD registry is based on an informatics technology platform, structured according to the most rigorous legal national and European requirements for management of patient sensitive data. A user-friendly web interface allows both direct patients and clinicians' participation. The platform's design permits expansion to incorporate new modules and new registries, and is suitable of interoperability with other international efforts. RESULTS: When the Italian NMD Registry was initiated, an ad hoc legal entity (NMD Registry Association) was devised to manage registries' data. Currently, several disease-specific databases are hosted on the platform. They collect molecular and clinical details of individuals affected by Duchenne or Becker muscular dystrophy, Charcot-Marie-Tooth disease, transthyretin type-familial amyloidotic polyneuropathy, muscle glycogen storage disorders, spinal and bulbar muscular atrophy, and spinal muscular atrophy. These disease-specific registries are at different stage of development, and the NMD Registry itself has gone through several implementation steps to fulfil different technical and governance needs. The new governance model is based on the agreement between the NMD Registry Association and the professional societies representing the Italian NMD clinical network. Overall, up to now the NMD registry has collected data on more than 2000 individuals living with a NMD condition. CONCLUSIONS: The Italian NMD Registry is a flexible platform that manages several condition-specific databases and is suitable to upgrade. All stakeholders participate in its management, with clear roles and responsibilities. This governance model has been key to its success. In fact, it favored patient empowerment and their direct participation in research, while also engaging the expert clinicians of the Italian network in the collection of accurate clinical data according to the best clinical practices.

Practical and clinical utility of non-invasive vagus nerve stimulation (nVNS) for the acute treatment of migraine: a post hoc analysis of the randomized, sham-controlled, double-blind PRESTO trial.

BACKGROUND: The PRESTO study of non-invasive vagus nerve stimulation (nVNS; gammaCore®) featured key primary and secondary end points recommended by the International Headache Society to provide Class I evidence that for patients with an episodic migraine, nVNS significantly increases the probability of having mild pain or being pain-free 2 h post stimulation. Here, we examined additional data from PRESTO to provide further insights into the practical utility of nVNS by evaluating its ability to consistently deliver clinically meaningful improvements in pain intensity while reducing the need for rescue medication. METHODS: Patients recorded pain intensity for treated migraine attacks on a 4-point scale. Data were examined to compare nVNS and sham with regard to the percentage of patients who benefited by at least 1 point in pain intensity. We also assessed the percentage of attacks that required rescue medication and pain-free rates stratified by pain intensity at treatment initiation. RESULTS: A significantly higher percentage of patients who used acute nVNS treatment (n = 120) vs sham (n = 123) reported a ≥ 1-point decrease in pain intensity at 30 min (nVNS, 32.2%; sham, 18.5%; P = 0.020), 60 min (nVNS, 38.8%; sham, 24.0%; P = 0.017), and 120 min (nVNS, 46.8%; sham, 26.2%; P = 0.002) after the first attack. Similar significant results were seen when assessing the benefit in all attacks. The proportion of patients who did not require rescue medication was significantly higher with nVNS than with sham for the first attack (nVNS, 59.3%; sham, 41.9%; P = 0.013) and all attacks (nVNS, 52.3%; sham, 37.3%; P = 0.008). When initial pain intensity was mild, the percentage of patients with no pain after treatment was significantly higher with nVNS than with sham at 60 min (all attacks: nVNS, 37.0%; sham, 21.2%; P = 0.025) and 120 min (first attack: nVNS, 50.0%; sham, 25.0%; P = 0.018; all attacks: nVNS, 46.7%; sham, 30.1%; P = 0.037). CONCLUSIONS: This post hoc analysis demonstrated that acute nVNS treatment quickly and consistently reduced pain intensity while decreasing rescue medication use. These clinical benefits provide guidance in the optimal use of nVNS in everyday practice, which can potentially reduce use of acute pharmacologic medications and their associated adverse events. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02686034 .

Recommendations for Improving the Quality of Rare Disease Registries.

Rare diseases (RD) patient registries are powerful instruments that help develop clinical research, facilitate the planning of appropriate clinical trials, improve patient care, and support healthcare management. They constitute a key information system that supports the activities of European Reference Networks (ERNs) on rare diseases. A rapid proliferation of RD registries has occurred during the last years and there is a need to develop guidance for the minimum requirements, recommendations and standards necessary to maintain a high-quality registry. In response to these heterogeneities, in the framework of RD-Connect, a European platform connecting databases, registries, biobanks and clinical bioinformatics for rare disease research, we report on a list of recommendations, developed by a group of experts, including members of patient organizations, to be used as a framework for improving the quality of RD registries. This list includes aspects of governance, Findable, Accessible, Interoperable and Reusable (FAIR) data and information, infrastructure, documentation, training, and quality audit. The list is intended to be used by established as well as new RD registries. Further work includes the development of a toolkit to enable continuous assessment and improvement of their organizational and data quality.