Characterising people with focal drug-resistant epilepsy: A retrospective cohort study.

OBJECTIVES: To describe the demographics, clinical characteristics, drug treatment outcomes, healthcare resource utilization, and injuries among people with focal drug-resistant epilepsy (F-DRE) analysed separately for six European countries. METHODS: We used electronic medical record data from six European (Belgium, Spain, Italy, France, UK and Germany) primary care/specialist care databases to identify antiseizure medication (ASM) treatment-naïve people (aged ≥ 18 years at F-DRE diagnosis). They were followed from their epilepsy diagnosis until death, the date of last record available, or study end. We used descriptive analyses to characterise the F-DRE cohort, and results were reported by country. RESULTS: One-thousand-seventy individuals with F-DRE were included (mean age 52.5 years; 55.4 % female). The median follow-up time from the first diagnosis to the end of the follow-up was 95.5 months across all countries. The frequency of F-DRE diagnosis in 2021 ranged from 8.8 % in Italy to 18.2 % in Germany. Psychiatric disorders were the most common comorbidity across all countries. Frequently reported psychiatric disorders were depression (26.7 %) and anxiety (11.8 %). The median time from epilepsy diagnosis to the first ASM failure ranged from 5.9 (4.2-10.2) months in France to 12.6 (5.8-20.4) months in Spain. Levetiracetam and lamotrigine were the most commonly used ASM monotherapies in all countries. Consultation with a general practitioner is sought more frequently after F-DRE diagnosis than after epilepsy diagnosis, except in the UK. SIGNIFICANCE: No one ASM is optimal for all people with F-DRE, and the risks and benefits of the ASM must be considered. Comorbidities must be an integral part of the management strategy and drive the choice of drugs.

Factors associated with sick leave duration in patients suffering from major depressive disorder initiating antidepressant treatment: a real-world evidence study in Germany and Spain.

OBJECTIVE: To describe MDD patients starting antidepressant (AD) treatment by pharmacological approach and identify factors associated with a longer sick leave (SL) duration. METHODS: Retrospective study on IQVIA German Disease Analyser (specialists) and Spanish Longitudinal Patient Database (general practitioners and specialists). MDD patients initiating AD treatment between July 2016-June 2018 were grouped by therapeutic approach (AD monotherapy vs. combination/switch/add-on) and their characteristics were analysed descriptively. Multiple logistic regression models were run to evaluate factors affecting SL duration (i.e., >30 days). RESULTS: One thousand six hundred and eighty-five patients (monotherapy: 58%; combination/switch/add-on: 42%) met inclusion criteria for Germany, and 1817 for Spain (monotherapy: 83%; combination/switch/add-on: 17%). AD treatment influenced SL duration: combination/switch/add-on patients had a 2-fold and a 4-fold risk of having >30 days of SL than monotherapy patients, respectively in Germany and Spain. Patients with a gap of time between MDD diagnosis and AD treatment initiation had a higher likelihood of experiencing a longer SL both in Germany and Spain (38% higher likelihood and 6-fold risk of having >30 days of SL, respectively). CONCLUSIONS: A careful and timely selection of AD treatment approach at the time of MDD diagnosis may improve functional recovery and help to reduce SL, minimising the socio-economic burden of the disease.Key pointsThe major depressive disorder has a substantial impact on work absenteeism.The present study aimed to describe MDD patients starting antidepressant (AD) treatment depending on the pharmacological approach and to identify factors associated with longer sick leave (SL) duration.Patients receiving AD monotherapy had a lower likelihood of having more than 30 days of sick leave than those receiving AD combination/switch/add-on.Patients for whom a gap of time between MDD diagnosis and initiation of AD treatment was observed, showed a higher likelihood of having more than 30 days of sick leave.Because findings from this analysis relied on secondary data, the authors would like to claim the urgency of conducting prospective observational studies that further investigate the effect that different AD therapeutic approaches and timely initiation of treatment might exert on patients' recovery.

Intravenous paracetamol in comparison with ibuprofen for the treatment of patent ductus arteriosus in preterm infants: a randomized controlled trial.

Our aim was to assess the efficacy and safety of intravenous (i.v.) paracetamol vs. i.v. ibuprofen for the treatment of hemodynamically significant patent ductus arteriosus (hsPDA) in preterm infants. This is a multicenter randomized controlled study. Infants with a gestational age of 25+0-31+6 weeks were randomized to receive i.v. paracetamol (15 mg/kg/6 h for 3 days) or i.v. ibuprofen (10-5-5 mg/kg/day). The primary outcome was the closure rate of hsPDA after the first treatment course with paracetamol or ibuprofen. Secondary outcomes included the constriction rate of hsPDA, the re-opening rate, and the need for surgical closure. Fifty-two and 49 infants received paracetamol or ibuprofen, respectively. Paracetamol was less effective in closing hsPDA than ibuprofen (52 vs. 78%; P = 0.026), but the constriction rate of the ductus was similar (81 vs. 90%; P = 0.202), as confirmed by logistic regression analysis. The re-opening rate, the need for surgical closure, and the occurrence of adverse effects were also similar.Conclusions: Intravenous paracetamol was less effective in closing hsPDA than ibuprofen, but due to a similar constriction effect, its use was associated with the same hsPDA outcome. These results can support the use of i.v. paracetamol as a first-choice drug for the treatment of hsPDA.Trial registration: Clinicaltrials.gov : NCT02422966, Date of registration: 04/09/2015; EudraCT no: 2013-003883-30. What is Known: • The successful closure of patent ductus arteriosus with oral paracetamol has been recently reported in several preterm infants, but only one randomized controlled study investigated the efficacy of intravenous paracetamol. What is New: • Intravenous paracetamol is less effective in closing hsPDA than ibuprofen, but have a similar constriction effect. • These results can support the use of i.v. paracetamol as a first-choice drug for the treatment of hsPDA.

Investigations on dose proportionality and drug-drug interaction for a fixed-dose combination of trazodone and gabapentin.

OBJECTIVES: To establish dose proportionality for trazodone and gabapentin at fixed ratios of trazodone/gabapentin 2.5/25, 10/100, and 30/300 and investigation of potential drug-drug interaction at a dose of 10/100. MATERIALS AND METHODS: 29 out of 30 healthy subjects completed this single-center, open-label, randomized, 5-period cross-over trial with single-dose fasted administrations. Administrations were separated by a washout period of at least 6 days. Blood samples were drawn until 48 hours post dose. A validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS) was applied for determination of trazodone and gabapentin in plasma. The lower limits of quantitation (LLOQ) were 1.00 ng/mL and 5.00 ng/mL for trazodone and gabapentin, respectively. Adverse events (AEs) were analyzed in the study population descriptively. RESULTS: Plasma concentrations were characterized thoroughly. For trazodone, assessment of proportionality (power model/pairwise-comparison by ANOVA) showed proportionality for AUC over all doses and for Cmax between the middle and high dose. For gabapentin, a less than proportional increase in both metrices was present with a likely proportional increase from 25 to 100 mg only. Considering common bioequivalence criteria, absence of pharmacokinetic interaction was confirmed comparing the combination and individual agents. 23 subjects experienced 53 AEs during the trial, the most frequent being fatigue (20 cases/15 subjects) and dizziness (14 cases/11 subjects). No serious AEs were reported. CONCLUSION: To our knowledge, for the first time, proportionality for trazodone at doses of 2.5 to 30 mg and for gabapentin at doses of 25 to 300 mg was investigated. Absence of a pharmacokinetic interaction was shown.

Predictors of sick leave days in patients affected by major depressive disorder receiving antidepressant treatment in general practice setting in Germany.

OBJECTIVE: To identify sick leave days (SLD) predictors after starting antidepressant (AD) treatment in patients affected by major depressive disorder (MDD), managed by general practitioners, with a focus on different AD therapeutic approaches. METHODS: Retrospective study on German IQVIA® Disease Analyser database. 19-64 year old MDD patients initiating AD treatment between July-2016 and June-2018 were grouped by therapeutic approach (AD monotherapy versus combination/switch/add-on). Data were analysed descriptively by AD therapeutic approach, while a zero-inflated Poisson (ZIP) multiple regression model was run to evaluate SLD predictors. RESULTS: 8,891 patients met inclusion criteria (monotherapy: 66%; combination/switch/add-on: 34%). All covariates had an influence on SLD after AD treatment initiation. Focussing on variables that physicians may more easily intervene to improve outcomes, it was found that the expected SLD number of combination/switch/add-on patients was 1.6 times that of monotherapy patients, and the expected SLD number of patients diagnosed with MDD before the decision to start AD treatment was 1.2 times that of patients not diagnosed with MDD. CONCLUSIONS: A patient tailored approach in the selection of AD treatment at the time of MDD diagnosis may improve functional recovery and help to reduce the socio-economic burden of the disease.KEY POINTSFew studies previously investigated the effect of antidepressant treatment approaches on sick leave days in major depressive disorder.To the authors' knowledge, this is the first study evaluating the effect of different antidepressant treatment approaches on sick leave days in major depressive disorder in German patients.Patients receiving antidepressant monotherapy treatment seemed to lose fewer working days than patients receiving antidepressants combination/switch/add-on therapy, both before and after starting treatment, even if differences were more pronounced after treatment has started.The use of antidepressant monotherapy or combination/switch/add-on therapy was the strongest predictor of sick leave days after starting antidepressant treatment: the expected number of sick leave days for the combination/switch/add-on group was 1.6 times that of the monotherapy group.Among factors associated with increased sick leave days, antidepressant therapeutic approach and the promptness of starting the antidepressant treatment when major depressive disorder is diagnosed, are those on which physicians may more easily intervene to improve outcomes.Findings from the present study suggest that a patient tailored approach may improve functional recovery and help reducing the socio-economic burden of the disease.

REACT expanded-access program in patients with metastatic renal cell carcinoma: real-world data from a European subanalysis.

AIM: RAD001 Expanded Access Clinical Trial (REACT) provided everolimus to patients with metastatic RCC before its commercial availability. This retrospective subgroup analysis evaluated eventual differences, mainly in safety, between the large European population (n = 906; 66.3%) and the overall population (n = 1367). PATIENTS & METHODS: REACT enrolled patients from 34 countries who received everolimus 10 mg/day until progression/discontinuation or commercial availability. RESULTS: Baseline characteristics, except race/ethnicity, were similar. Incidences of grade 3/4 adverse events were 50.7/11.3% in the European population and 48.8/12.8% in the overall population. A similar percentage of the European and overall populations achieved stable disease (∼ 51%) and completed treatment (20.6 and 19.7%). CONCLUSION: These results do not suggest differences for the European population and support everolimus as a worldwide standard of care for VEGFR-refractory metastatic RCC (NCT00655252).

Impact of trazodone once-a-day on quality of life and functional recovery in adults with major depressive disorder: A prospective, observational study.

BACKGROUND: Health-related quality of life (HRQL) is an important goal for patients with major depressive disorder (MDD), but whether antidepressants improve HRQL in these patients is unclear. Here, we describe the real-world effects of trazodone once-a-day (TzOAD) and selective serotonin reuptake inhibitor (SSRI) treatments on HRQL and functioning in adults with MDD. METHODS: This 8-week prospective, observational, open-label, multicenter study was conducted in adults with moderate or severe MDD for whom TzOAD or SSRI were prescribed as monotherapy. The primary outcome was life enjoyment and satisfaction assessed via the patient-reported Quality-of-Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) from baseline to week 8. Secondary outcomes included change in Q-LES-Q-SF from baseline to weeks 1 and 2; severity of depressive symptoms using the Montgomery Åsberg Depression Rating Scale (MADRS) and sleep disturbance via the PROMIS SF-SD 8b questionnaire at weeks 1, 2, and 8; and overall functioning via the Sheehan Disability Scale (SDS), hedonic capacity using the Snaith-Hamilton Pleasure Scale (SHAPS), and cognitive dysfunction using the Perceived Deficits Questionnaire (PDQ-5) at baseline and week 8. RESULTS: The study included 208 adults with MDD (mean [SD] age = 50.2 [14.3] years; 68.6% female; 98.4% White). Life enjoyment and satisfaction improved from baseline to week 8 for both treatment groups: Q-LES-Q-SF mean (SD) scores were 27.5 (20.4) for the SSRI group and 39.0 (22.1) for the TzOAD group. Depressive symptoms and sleep disturbances also reduced from baseline to week 8: MADRS (SSRI, -15.7 [8.3]; TzOAD, -21.0 [9.8]); PROMIS SF-SD 8b (SSRI, -9.9 [12.6]; TzOAD, -22.0 [12.6]). Mean change scores in Q-LES-Q-SF, MADRS, and PROMIS SF-SD 8b improved as early as week 1 in both groups. Mean scores also improved from baseline to week 8 on SDS (SSRI, -9.2 [7.4]; TzOAD, -14.3 [7.5]), SHAPS (SSRI, -6.6 [4.3]; TzOAD, -8.3 [4.4]), and PDQ-5 (SSRI, -5.8 [4.5]; TzOAD, -7.7 [5.0]). CONCLUSIONS: In adults with MDD who received TzOAD or SSRIs, overall and individual HQRL domains improved rapidly and in parallel with improvements in depressive symptoms, with a slightly greater improvement observed in the TzOAD group.

Dalbavancin real-life utilization among diabetic patients suffering from infections in Italy and Spain: The DALBADIA retrospective cohort study.

OBJECTIVES: To retrospectively describe the patterns of use of dalbavancin for treating infections in diabetic patients in Italian and Spanish standard clinical practice. METHODS: DALBADIA [NCT04959799] was a multicentre, observational, retrospective cohort study, conducted in Italy and Spain. The study enrolled 97 adults with type 1 or 2 diabetes mellitus, treated with dalbavancin as per standard clinical practice for a Gram-positive bacterial infection or the Gram-positive component of a mixed infection. RESULTS: Dalbavancin was used to treat cellulitis (18/92 patients, 19.6%), followed by prosthetic joint infection (14 patients, 15.2%), endocarditis (13 patients, 14.1%), and primary bacteraemia (10 patients, 10.9%); 78/92 (84.8%) patients had Gram-positive infections only, and 14 (15.2%) had mixed infections. The most frequently isolated microorganisms were Staphylococcus aureus in 43 (55.8% of the patients with microbial isolation), 25.6% of which methicillin-resistant; Staphylococcus epidermidis in 13 (16.9%), 53.8% of which methicillin-resistant; Enterococcus faecalis in 11 (14.3%). The main reason for the dalbavancin choice was the intent to simplify the antibiotic regimen (81.5% of cases). A multidisciplinary team participated in the treatment choice process for 53 (57.6%) patients. Dalbavancin was given as first-line antibiotic in 34 (37.0%) patients and administered as one infusion in 32 (34.8%), and as two infusions in 39 (42.4%). In total, 57/62 (91.9%) eligible patients with available assessment were judged clinically cured or improved at the end of observation. CONCLUSION: In clinical practice, dalbavancin was used in diabetic patients to treat ABSSSIs and other difficult-to-treat infections with a favourable safety profile and a high rate of positive clinical responses.

Efficacy and Safety of Trazodone and Gabapentin Fixed-Dose Combination in Patients Affected by Painful Diabetic Neuropathy: Randomized, Controlled, Dose-Finding Study.

INTRODUCTION: Up to 50% of diabetic patients with neuropathy suffer from chronic pain, namely painful diabetic neuropathy (PDN), an unmet medical need with significant impact on quality of life. Gabapentin is widely used for PDN, albeit with frequent dose-limiting effects. Trazodone, an antidepressant with multi-modal action, has shown promising results when given at low doses as an add-on to gabapentin. Upon previous clinical trials and experimental evidence, a fixed-dose combination (FDC) of both compounds, at low doses, was developed for neuropathic pain. METHODS: This was a phase II, randomized, double-blind, placebo and reference controlled, dose-finding, multicenter, international, prospective study. Male and female diabetic patients aged 18-75 years and affected by PDN were eligible for enrolment. Patients were randomized (1:1:1:1:2 ratio) to trazodone and gabapentin (Trazo/Gaba) 2.5/25 mg t.i.d. for 8 weeks, Trazo/Gaba 5/50 mg t.i.d. for 8 weeks, Trazo/Gaba 10/100 mg t.i.d. for 8 weeks, gabapentin (Gaba), or placebo (PLB). The aim of the study was to collect preliminary information on the effect of the 3 different FDCs of Trazo/Gaba on pain intensity based on the 11-point numeric rating score (NRS) after 8 weeks of treatment. The secondary objectives were the evaluation of the percentage of responders, neuropathic pain symptoms, anxiety, sleep, quality of life, safety, and tolerability. The primary efficacy endpoint was evaluated with last observation carried out forward (LOCF), using an analysis of covariance (ANCOVA), including treatment and centers as factors and baseline as covariate and applying linear contrast test, excluding the active treatment. Only if the linear contrast test was significant (p < 0.05), the step-down Dunnett test would be used to determine the minimum effective dose significantly different from PLB. If linearity was not verified, an adjusted ANCOVA model and comparisons with Dunnett test were performed. Before the application of the ANCOVA model, the non-significance of interaction treatment per baseline was verified. RESULTS: A total of 240 patients were included in the modified intention-to-treat (m-ITT) population: 39 in Trazo/Gaba 2.5/25 mg, 38 in Trazo/Gaba 5/50 mg, 37 in Trazo/Gaba 10/100 mg, 83 in PLB, and 43 in Gaba. After 8 weeks of treatment, changes of the average daily pain score based on the 11-point NRS from baseline were - 2.52 ± 2.31 in Trazo/Gaba 2.5/25 mg group, - 2.24 ± 1.96 in Trazo/Gaba 5/50 mg group, - 2.46 ± 2.12 in Trazo/Gaba 10/100 mg group, - 1.92 ± 2.21 in Gaba group, and - 2.02 ± 1.95 in the PLB group. The linear contrast test did not result in significant differences (p > 0.05) among treatment groups. Consequently, the minimum effective dose against PLB was not determined. The multiple comparison with Dunnett adjustment did not show any statistically significant differences vs. PLB after 8 weeks of treatment: Trazo/Gaba 2.5/25 mg (95% confidence interval (CI) - 1.2739, 0.2026; p = 0.1539); Trazo/Gaba 5/50 mg (95% CI - 0.9401, 0.5390; p = 0.5931); Trazo/Gaba 10/100 mg (95% CI - 1.0342, 0.4582; p = 0.4471). However, patients receiving the lowest dose of Trazo/Gaba 2.5/25 mg showed a statistically significant difference to PLB after 6 weeks of treatment (95% CI - 1.6648, - 0.2126; p = 0.0116). Positive results were also found for responder patients, other items related to the pain, anxiety, depression, sleep, and quality of life, consistently in favor to the lowest Trazo/Gaba FDC. Two serious adverse events (SAEs) occurred but were judged unrelated to the study treatment. Treatment-emergent adverse events (TEAEs) were mainly mild-to-moderate in intensity and involved primarily nervous system, gastrointestinal disorders, and investigations. CONCLUSIONS: The primary end point of the study was the change from baseline of the average daily pain score based on the 11-point NRS after 8 weeks of treatment. While the primary endpoint was not reached, patients treated with Trazo/Gaba 2.5/25 mg t.i.d. showed statistically significant improvement of pain and other scores after 6 weeks and reported consistent better results in comparison to PLB on primary and secondary endpoints for the overall study duration. According to these results, the lowest dose of Trazo/Gaba FDC may be the best candidate for further clinical development to confirm the potential benefits of the FDC drug for this condition. CLINICAL TRIAL REGISTRATION: NCT03749642.

Comparative evaluation of rapidity of action of benzydamine hydrochloride 0.3% oromucosal spray and benzydamine hydrochloride 3 mg lozenges in patients with acute sore throat: A phase IV randomized trial.

BACKGROUND: Acute sore throat (ST) can occur as part of a common cold of viral origin or caused by pharyngeal bacterial pathogens. The majority of patients with acute ST complain of pain on swallowing and dry scratchiness which can have a negative impact on the quality of life (QoL). This study aimed to evaluate the time to pain relief in patients with acute ST, following a single administration of benzydamine hydrochloride (HCl) 0.3% oromucosal spray or benzydamine HCl 3 mg lozenges. METHODS: This multicenter, randomized, active-controlled, open label, parallel-group, international phase IV study was conducted at 12 investigational centers in Poland, Hungary, and Russian Federation. The study population consisted of 363 adult patients with recent onset (≤3 days) of ST and a diagnosis of tonsillopharyngitis. The primary endpoint was to assess the efficacy of benzydamine HCl in ST pain relief at 2 minutes after a single-dose administration. Secondary endpoints included, among others, the assessment of a first perceived ST relief at 1 minute after a single-dose administration of benzydamine HCl spray or lozenge. RESULTS: Both the spray and lozenges are effective in providing a ST relief starting already at 2 minutes after a single administration, with an effect lasting up to up to 4 hours. Clinical efficacy after 7 days of treatment and a good safety profile were also demonstrated. CONCLUSION: Anesthetic and analgesic properties of benzydamine spray and lozenges effectively addressed the patient priority of a rapid relief of symptoms of upper respiratory tract infections (URTI).

An Observational Pilot Study using a Digital Phenotyping Approach in Patients with Major Depressive Disorder Treated with Trazodone.

This 8-week study was designed to explore any correlation between a passive data collection approach using a wearable device (i.e., digital phenotyping), active data collection (patient's questionnaires), and a traditional clinical evaluation [Montgomery-Åsberg Depression Rating Scale (MADRS)] in patients with major depressive disorder (MDD) treated with trazodone once a day (OAD). Overall, 11 out of 30 planned patients were enrolled. Passive parameters measured by the wearable device included number of steps, distance walked, calories burned, and sleep quality. A relationship between the sleep score (derived from passively measured data) and MADRS score was observed, as was a relationship between data collected actively (assessing depression, sleep, anxiety, and warning signs) and MADRS score. Despite the limited sample size, the efficacy and safety results were consistent with those previously reported for trazodone. The small population in this study limits the conclusions that can be drawn about the correlation between the digital phenotyping approach and traditional clinical evaluation; however, the positive trends observed suggest the need to increase synergies among clinicians, patients, and researchers to overcome the cultural barriers toward implementation of digital tools in the clinical setting. This study is a step toward the use of digital data in monitoring symptoms of depression, and the preliminary data obtained encourage further investigations of a larger population of patients monitored over a longer period of time.

Long-Term Treatment with Trazodone Once-A-Day (TzOAD) in Patients with MDD: An Observational, Prospective Study.

Purpose: This was an observational, prospective, single-group, multicentre, international study aimed to describe the clinical response, functional impairment, and quality of life (QoL) of patients suffering from major depressive disorder (MDD) and in treatment with Trazodone Once-A-Day (TzOAD) monotherapy, over a 24-week period. Patients and Methods: A total of 200 patients with a diagnosis of MDD who had been treated with TzOAD monotherapy were enrolled from 26 sites across 3 European countries (Bulgaria, Czech Republic, and Poland), including psychiatric private practices, and outpatient departments from general and psychiatric hospitals. Study assessments were completed by physicians and patients during routine visits within the normal practice of care. Results: Clinical response was assessed by Clinical Global Impressions - Improvement (CGI-I) responders' percentage at 24 (±4) weeks. The majority of patients (86.5%) reported an improvement on the CGI-I compared to baseline. Results of the study confirm the well-known safety and tolerability of TzOAD, as well as its effectiveness on depressive symptoms, such as improvement in QoL, sleep quality, and overall functioning accompanied by favourable adherence and low drop-out rate. Conclusion: To our knowledge, this is the first observational, long-term study in patients suffering from MDD, conducted with TzOAD. The improvement observed in clinical response, overall functioning, depressive symptoms, and QoL along the 24 weeks (+4) maintenance period and the very good retention rate, suggest that TzOAD may represent an effective and well tolerated treatment option for patients suffering from MDD.

REDS study: Retrospective effectiveness study of dalbavancin and other standard of care of the same IV antibiotic class in patients with ABSSSI.

OBJECTIVES: Acute bacterial skin and skin-structure infections (ABSSSIs) are a common source of morbidity in both the community and hospital settings. The current standard of care (SoC) requires multiple-dose intravenous (IV) regimens, which are associated with high hospitalisation rates, concomitant event risks and costs. Dalbavancin is a lipoglycopeptide, long-acting antibiotic that is effective against Gram-positive microorganisms, including methicillin-resistant Staphylococcus aureus (MRSA). Dalbavancin allows treatment of ABSSSIs with a single-shot IV administration or once weekly for 2 weeks, enabling clinicians to treat patients in an outpatient setting or to shorten the length of hospital stay. METHODS: This multicentre, observational, retrospective study compared hospitalised patients who received dalbavancin and patients treated with the three most used IV antibiotics of the same or similar class: vancomycin, teicoplanin and daptomycin. The primary outcome was the time to discharge after starting the study antibiotics. RESULTS: The primary endpoint, time to discharge from the study therapy start, was measured for both groups: the median number of days was 6.5 in the dalbavancin group vs. 11.0 days in the SoC group. Moreover, in subpopulations of patients receiving one or more concomitant antibiotics active for Gram-positives, MRSA and patients with the most prevalent comorbidity (i.e., diabetes), the advantage of dalbavancin in terms of length of stay was confirmed, with a halved time to discharge or more. Safety data on dalbavancin were consistent with data collected in clinical trials. No serious adverse drug reactions related to dalbavancin were reported and most of them were classified as skin and subcutaneous tissue disorders. One serious ADR was reported for daptomycin. CONCLUSIONS: Although the analysis was only descriptive, it can be concluded that dalbavancin may enable a remarkable reduction in length of hospital stay, also confirming the clinical effectiveness and good safety profile demonstrated in clinical trials in a real-world setting.

Efficacy and safety of lurasidone in schizophrenia: pooled analysis of European results from double-blind, placebo-controlled 6-week studies.

The objective of this study is to confirm the efficacy and safety of lurasidone in the acute treatment of schizophrenia in European patients. Data were pooled from three studies of patients randomized to 6 weeks of double-blind, placebo-controlled, fixed-dose (40/80 mg and 120/160 mg) lurasidone. The primary efficacy endpoint was a week 6 change in the Positive and Negative Syndrome Scale (PANSS) total score and secondary endpoints included the Clinical Global Impression, Severity scale (CGI-S). In total 328 safety patients were enrolled; 72.6% were completers. Endpoint change was significantly greater in patients treated with 40-80 mg/d and 120-160 mg/d compared to placebo on the PANSS total score ( P < 0.001) and the CGI-Severity score ( P < 0.001) for all comparisons. For PANSS total scores, endpoint effect sizes for lurasidone 40-80 mg/d and 120-160 mg/d were 0.68 to 0.77, respectively. Adverse events with a frequency ≥5% (and were greater than for combined lurasidone) were insomnia (11.7%), akathisia (11.3%), headache (7.4%), Parkinsonism (6.5%) and nausea (5.7%). Median changes (in mg/dL) at endpoint were minimal for total cholesterol (-8.0); triglycerides (-8.5) and glucose (-2.0) and in mean weight (-0.2 kg). In European patients with schizophrenia, short-term treatment with lurasidone in doses of 40-160 mg/d was generally safe, well-tolerated and effective with minimal effects on weight and metabolic parameters.

Real-World Characteristics and Treatment Patterns of Patients With Insomnia Prescribed Trazodone in the United States.

PURPOSE: This study sought to describe patient characteristics and treatment patterns among patients with insomnia prescribed trazodone in the United States. METHODS: This real-world, retrospective, descriptive cohort study used US commercial insurance claims from July 1, 2009, through June 30, 2019. The index date was the first prescription for trazodone between January 1, 2010, and December 31, 2018, with 6 months for the preindex period and ≥6 months for the postindex period. FINDINGS: Among 5.8 million patients with insomnia, 17.7% were prescribed trazodone, and 357,380 adults (6.2%) and 7564 children (0.1%) met the study eligibility criteria. The mean (SD) age was 48.8 (15.8) years for adults and 14.8 (2.7) years for pediatrics. Most patients were female (229,280 adults [64.2%] and 4481 children [59.2%]). Insomnia due to mental disorder was the most common specific diagnosis. The most common (>25%) comorbid conditions were anxiety, depression, and hypertensive disease, and 1 of 10 had a history of substance abuse. Zolpidem was previously prescribed (73,342 adults [20.5%] and 233 children [3.1%]) and continued to be prescribed. Concomitant antidepressants were most common (216,893 adults [60.7%] and 5414 children [71.6%]), but benzodiazepines (132,740 adults [37.1%] and 1188 children [15.7%]), antiepileptics (115,064 adults [32.2%] and 2103 children [27.8%]), nonbenzodiazepines (90,946 adults [25.4%] and 542 children [7.2%]), and antipsychotics (40,490 adults [11.3%] and 2063 children [27.3%]) were also prescribed. IMPLICATIONS: This study provides current evidence that trazodone use is widespread among patients with insomnia and is often associated with other specific comorbidities, such as psychiatric conditions. A deeper knowledge of the real-world management of patients with insomnia may facilitate steps toward improving sleep quality, daytime functioning, and clinical outcomes for patients.

Clinical evaluation of switching from immediate-release to prolonged-release lithium in bipolar patients, poorly tolerant to lithium immediate-release treatment: A randomized clinical trial.

AIM: The effect of switching from lithium immediate release (Li-IR) to lithium prolonged release (Li-PR) on lithium-induced tremor after 1 and 12 weeks of treatment was evaluated in a randomized, multicenter, open trial, in bipolar patients from the participating sites with a tremor severity ≥2 (Udvalg for Kliniske Undersøgelser [UKU] rating scale) despite optimal lithium titration. METHODS: The primary endpoint was the evaluation of tremor by means of the UKU scale after 1 week of treatment. Secondary endpoints included manic Young Mania Rating Scale (YMRS) and depressive symptoms (Montgomery-Asberg Depression Rating Scale), a global assessment of the patient's status (Clinical Global Impression), polyuria/polydipsia (UKU item 3.8) and patient-reported outcomes. RESULTS: Owing to difficulties in including suitable patients the enrollment phase was closed when 73 patients were randomized. Notwithstanding the lower number of patients, in the modified intention-to-treat population (n = 70) the primary endpoint was statistically significant: tremor improved after 1 week in 62.9% in Li-PR group against 20.0% of patients in Li-IR group (p = .0006; two-tailed Fisher's exact test). The difference remained statistically significant after 4 (p = .0031) and 12 weeks (p = .0128). The same analysis performed in the PP population confirmed these results. Among the secondary endpoints, only the factor convenience of the treatment satisfaction questionnaire showed a statistically significant difference between groups. There were no apparent differences in the safety profile of the two formulations. CONCLUSIONS: This study is the first comparative documentation of a potential benefit of the prolonged-release formulation in reducing the symptom tremor, a well-known adverse effect of lithium therapy. Indeed, the study results should be interpreted taking into account the sample size lower than planned.

Efficacy and safety of lurasidone in adolescents and young adults with schizophrenia: A pooled post hoc analysis of double-blind, placebo-controlled 6-week studies.

BACKGROUND: The aim of this pooled analysis was to evaluate the efficacy and safety of lurasidone in the treatment of an acute exacerbation of schizophrenia in adolescents and young adults. METHODS: The six pooled studies in this analysis used similar study designs and outcome measures. Patients (aged 13-25 years) were randomized to 6 weeks of double-blind, placebo-controlled treatment with lurasidone in fixed doses of 40, 80, 120, or 160 mg. The primary efficacy endpoint was Week 6 change in the Positive and Negative Syndrome Scale (PANSS) total score; secondary efficacy endpoints included Week 6 change in the Clinical Global Impression-Severity scale. RESULTS: The safety population consisted of 537 patients (mean age: 18.1 years); 82.6% of patients completed the studies. Treatment with lurasidone was significantly better than placebo at all doses (p < 0.001) for change in the PANSS total score at Week 6. Placebo-adjusted PANSS scores ranged from -9.4 to -16.1 (effect sizes: 0.53-0.90), with effect sizes increasing at higher doses. For lurasidone (combined doses), three adverse events occurred with a frequency of ≥5% (nausea: 13.5%; somnolence: 12.1%; akathisia: 10.1%). At last observation carried forward (LOCF)-endpoint weight gain of ≥7% was similar for lurasidone versus placebo (3.6 vs. 4.7%). Minimal median changes were observed at endpoint in cholesterol, -2.0 mg/dL; triglycerides, 0.0 mg/dL; and glucose, 0.0 mg/dL. CONCLUSIONS: In adolescents and young adults with schizophrenia, treatment with lurasidone in doses of 40-160 mg/d was a safe, well-tolerated, and effective treatment. Short-term treatment with lurasidone was associated with minimal effects on weight and metabolic parameters.

Impact of Lurasidone and Other Antipsychotics on Body Weight: Real-World, Retrospective, Comparative Study of 15,323 Adults with Schizophrenia.

PURPOSE: The primary objectives were to describe weight changes following initiation of lurasidone versus other antipsychotics and estimate the risk of clinically relevant (≥7%) weight changes. PATIENTS AND METHODS: This retrospective, longitudinal comparative cohort study was based on electronic medical records (EMRs) of United States (US) adult patients with schizophrenia who were prescribed lurasidone or other antipsychotics as monotherapy between 1 April 2013 and 30 June 2019. RESULTS: Overall, the study included 15,323 patients with a diagnosis of schizophrenia; 6.1% of patients received lurasidone, 60.4% received antipsychotics associated with a medium-high risk of weight gain (clozapine, olanzapine, quetiapine, risperidone, paliperidone) and 33.5% received antipsychotics with a low risk of weight gain (aripiprazole, first-generation antipsychotics, ziprasidone). Lurasidone was associated with the smallest proportion of patients experiencing clinically relevant weight gain and the greatest proportion of patients with clinically relevant weight loss. The risk of clinically relevant weight gain was numerically higher with all antipsychotics versus lurasidone and was statistically significant for olanzapine (hazard ratio [HR]=1.541; 95% confidence interval [CI]=1.121; 2.119; p=0.0078) versus lurasidone. The likelihood of ≥7% weight loss was significantly greater with lurasidone versus all antipsychotics (p<0.05), except ziprasidone. CONCLUSION: This real-world study suggests that lurasidone has a lower risk of clinically relevant weight gain and a higher likelihood of clinically relevant weight loss than other commonly used antipsychotics.

Management and Treatment of Patients With Major Depressive Disorder and Chronic Diseases: A Multidisciplinary Approach.

In patients with physical chronic diseases, the prevalence of major depressive disorder (MDD) is approximately 2- to 3-fold higher than in the general population, and it can reach up to 20-40%. The comorbidity of MDD with chronic medical diseases is associated with poorer quality of life, increased medical symptom burden, poor adherence to self-care regimens, increased risk of functional impairment, morbidity, and mortality, and also higher medical costs. Despite this evidence, in routine practice, psychological issues and concerns are frequently inadequately managed. This consensus document proposes that a proper diagnosis, a multidisciplinary approach, and a personalized treatment plan would allow patients with MDD and chronic comorbidities to be more compliant, to improve the outcomes, to reduce possible relapses in the long term, and to prevent or better manage complications and adverse events. This proposal might be useful for any health professionals who deal with patients with chronic diseases, as it can help to pay more attention to the emotional impact of these conditions, in particular in terms of depressive symptoms.

Efficacy and Safety of Low Doses of Trazodone in Patients Affected by Painful Diabetic Neuropathy and Treated with Gabapentin: A Randomized Controlled Pilot Study.

BACKGROUND: Painful diabetic neuropathy is an important therapeutic challenge as the efficacy of analgesic drugs in this setting is still unsatisfactory. Monotherapy with available treatments is often not sufficient and a combination of drugs is necessary. Trazodone (TRZ) is a compound with a multi-modal mechanism of action, being a serotonin-2 antagonist/reuptake inhibitor developed and approved for the treatment of depression in several countries. Previous clinical trials suggest a possible beneficial effect of low doses of trazodone for the treatment of patients affected by painful diabetic neuropathy. OBJECTIVE: This phase II study was designed to collect data on the efficacy and safety of low doses of TRZ combined with gabapentin after 8 weeks of treatment in patients affected by painful diabetic neuropathy. METHODS: This was a randomized, double-blind, placebo-controlled, multi-center, international, prospective study. Male and female diabetic patients aged 18-75 years and affected by painful diabetic neuropathy were eligible for enrollment. Subjects were randomized (1:1:1 ratio) to TRZ30 (10 mg three times daily for 8 weeks) or TRZ60 (20 mg three times daily for 8 weeks) or placebo. Gabapentin as background therapy was administered in open-label conditions to all patients. The primary endpoint was the change from baseline of the Brief Pain Inventory Short Form item 5 to week 8. Secondary endpoints included the other Brief Pain Inventory Short Form items, and the assessment of anxiety, sleep, quality of life, patient's improvement, and safety. RESULTS: One hundred and forty-one patients were included in the intention-to-treat population: 43 allocated to the TRZ30 group, 50 to the TRZ60 group, and 48 to the placebo group. After 8 weeks, the mean changes of Brief Pain Inventory Short Form item 5 from baseline were - 3.1, - 2.6, and - 2.5 in the TRZ30, TRZ60, and placebo groups, respectively. No statistically significant differences between groups were seen. Nevertheless, a better trend was observed for TRZ30 vs placebo (95% confidence interval - 1.30, 0.15; p = 0.1179), on top of the background effect of gabapentin administered to all study groups. 62.8% of patients achieved a ≥ 50% reduction in the TRZ30 group, 54% in the TRZ60 group, and 45.8% in the placebo group. At the same time, a statistically significant improvement was observed in Brief Pain Inventory Short Form item 6 for TRZ30 vs placebo (95% confidence interval - 1.54, - 0.07; p = 0.0314). No serious adverse event occurred during the trial and the most frequent treatment-emergent adverse events involved nervous system, QT prolongation, and gastrointestinal disorders. CONCLUSIONS: All treatment groups showed a clinically meaningful pain improvement; nevertheless, patients in the TRZ30 treatment group reported better efficacy outcomes. This finding suggests that low doses of TRZ could be useful for treating painful diabetic neuropathy, and support further adequately powered confirmatory trials investigating the efficacy of TRZ. CLINICAL TRIAL REGISTRATION: NCT03202979, date of registration: 29/06/2017.