Double-blind Multicenter Trial Research Articles

On the Possibility of Using the Topical form of the Recombinant Interferon alpha-2b Drug in the Prevention of Acute Respiratory Viral Infections in Organized Groups

Relevance. Respiratory infections are an urgent problem for organized groups, including military ones, since the transmission of pathogens by airborne droplets and household contact routes, physical and psychological stress on adaptive mechanisms contribute to the development of the epidemic process. There is no doubt that vaccination makes a significant contribution to the prevention of respiratory infections, but the contingent remains vulnerable to other pathogens against which there are no vaccines. Therefore, the search for new methods of non-specific prevention is necessary in maintaining the health of persons permanently residing in collectives. Aim. Evaluation of the possibility of using the topical form of the recombinant interferon α-2b drug for the prevention of acute respiratory viral infections in organized groups. Materials and methods. The work was carried out according to the methodology of a multicenter (3 Centers) double-blind controlled trial involving 3,235 people aged 18 to 22 years, who were divided into three groups: 1 gy. - received a recombinant interferon α-2b (Grippferon) drug 3 drops in each nasal passage 2 times a day in for two weeks; 2 g. - saline solution intranasally according to the same scheme; 3 g. - the volunteers did not receive anything. The frequency of respiratory infections was studied. Results and discussion. Medical monitoring of the study participants, which was carried out for 2 months, showed that in the groups from the Center 1, the incidence of acute respiratory diseases for 2 months in the main group (gr. 1) was 2.3 times lower than in the control (gr. 2) and the comparison group (gr. 3). In the Center 2 The data corresponded to the dynamics of Center 1: the incidence values were 2.4-2.5 times lower in Group 1. In Center 3, the values were 2.0-2.1, respectively. The epidemic effect of intranasal administration of the topical form of the drug recombinant interferon α-2b is due to its effect on the factors of mucosal immunity, which contributes to non-specific protection and increased body resistance against respiratory infections. Conclusions. The presented advantages of the recombinant interferon α-2b drug make it possible to draw attention to the clinical feasibility of its use for preventive purposes in organized groups, including military ones, from the position of high epidemiological effectiveness, both pre-exposure and post-exposure prevention of acute respiratory viral infections.

The effect of sustained-release CARvedilol in patients with hypErtension and heart failure with preserved ejection fraction: a study protocol for a pilot randomized controlled trial (CARE-preserved HF).

Although beta-blockers improve clinical outcomes in heart failure with reduced ejection fraction, the benefit of beta-blockers in heart failure with preserved ejection fraction (HFpEF) is uncertain. Global longitudinal strain (GLS) is a robust predictor of heart failure outcomes, and recent studies have shown that beta-blockers are associated with improved survival in those with low GLS (GLS <14%) but not in those with GLS ≥14% among patients with LVEF ≥40%. Therefore, the objective of this trial is to evaluate the effect of sustained-release carvedilol (carvedilol-SR) on the outcome [N-terminal pro-B-natriuretic peptide (NT-proBNP) concentration] in patients with hypertension and HFpEF and will assess the differential effects of these drugs on the outcome, according to the GLS categories. This prospective randomized double-blind multicenter trial (CARE-preserved HF) will include 100 patients with HFpEF from three tertiary hospitals in South Korea. Patients with HFpEF and hypertension aged ≥20 years who have evidence of functional and structural heart disease on echocardiography and elevated natriuretic peptide will be enrolled. Eligible participants will be randomized 1:1 to either the carvedilol-SR group (n = 50) or the placebo group (n = 50). Patients in the carvedilol-SR group will receive 8, 16, 32, or 64 mg carvedilol-SR once daily for 6 months, and the dose of carvedilol will be up-titrated at the discretion of the treating physicians. The primary efficacy outcome was the time-averaged proportional change in N-terminal pro-B-natriuretic peptide concentration from baseline to months 3 and 6. We will also evaluate the differential effects of carvedilol-SR on primary outcomes according to GLS, using a cut-off of 14% or the median value. This randomized controlled trial will investigate the efficacy and safety of carvedilol-SR in patients with HFpEF and hypertension. ClinicalTrial.gov, identifier NCT05553314.

Erector spinae plane block did not improve postoperative pain-related outcomes and recovery after video-assisted thoracoscopic surgery : a randomised controlled double-blinded multi-center trial

IntroductionThere is a sizable niche for a minimally invasive analgesic technique that could facilitate ambulatory video-assisted thoracoscopic surgery (VATS). Our study aimed to determine the analgesic potential of a single-shot erector spinae plane (ESP) block for VATS. The primary objective was the total hydromorphone consumption with patient-controlled analgesia (PCA) 24 h after surgery.MethodsWe conducted a randomized, controlled, double-blind study with patients scheduled for VATS in two major university-affiliated hospital centres. We randomized 52 patients into two groups: a single-shot ESP block using bupivacaine or an ESP block with normal saline (control). We administered a preoperative and postoperative (24 h) quality of recovery (QoR-15) questionnaire and assessed postoperative pain using a verbal numerical rating scale (VNRS) score. We evaluated the total standardized intraoperative fentanyl administration, total postoperative hydromorphone consumption (PCA; primary endpoint), and the incidence of adverse effects.ResultsThere was no difference in the primary objective, hydromorphone consumption at 24 h (7.6 (4.4) mg for the Bupivacaine group versus 8.1 (4.2) mg for the Control group). Secondary objectives and incidence of adverse events were not different between the two groups at any time during the first 24 h following surgery.ConclusionOur multi-centre randomized, controlled, double-blinded study found no advantage of an ESP block over placebo for VATS for opioid consumption, pain, or QoR-15 scores. Further studies are ongoing to establish the benefits of using a denser block (single-shot paravertebral with a continuous ESP block), which may provide a better quality of analgesia.

Results of a randomized double-blind multicenter clinical trial of the efficacy and safety of the drug riamilovir for the prevention of COVID-19

Evaluation of the efficacy and safety of riamilovir as a drug for the prevention of coronavirus infection (COVID-19) in adults who have constant contact with COVID-19 patients as a result of living together. The study included 750 adult participants living with patients with confirmed polymerase chain reaction method COVID-19, who had a negative polymerase chain reaction result for the SARS-CoV-2 virus at the initial level, met the criteria for inclusion, non-inclusion and exclusion, and signed a voluntary informed consent to participate in a clinical trial. The efficacy, good tolerability and safety of the drug riamilovir for the prevention of COVID-19 infection among people who have come into contact with COVID-19 patients in a family focus of infection have been established. As a result of a multicenter randomized double-blind clinical trial, the effectiveness of the drug riamilovir for the prevention of COVID-19 infection was established. It was shown that the relative risk of disease in the group taking riamilovir for prophylaxis was 88.96% lower than in the control group. Based on the results of a clinical trial, in October 2023 Ministry of Health of the Russian Federation approved the inclusion of a new indication (prophylaxis of COVID-19 infection) in the instructions for the medical use of the drug riamilovir (trade name - Triazavirin®).

Clinical trial of tolerability, safety and immunogenicity of influenza inactivated split-vaccine Flu-M in children aged 6 to 17 years

Purpose. To evaluate the tolerability, safety and immunogenicity of influenza inactivated split flu vaccine Flu-M during single immunization of children aged 6 to 17 years.Materials and methods. A multicentre double-blind comparative randomised clinical trial of influenza inactivated split vaccine Flu-M for immunisation of children aged 6 to 17 years (the reference agent – Ultrix vaccine) was conducted. Children aged 12 to 17 years inclusive (300 children) were studied at stage I, and children aged 6 to 12 years (300 children) at stage II. Volunteers of each age category were randomised 1:1 into 2 groups comparable in sex and age, one was vaccinated with Flu-M vaccine and the other with Ultrix vaccine. The follow-up, including various laboratory and clinical tests, lasted for 28 days from the time of vaccination.Results. Both vaccines were well tolerated by children aged 12 to 17 years and by children aged 6 to 12 years. There were no severe or serious adverse events. By all criteria of immunogenicity evaluation, vaccine Flu-M was not inferior to the comparison vaccine Ultrix.Conclusion. Influenza inactivated split Flu-M vaccine produced by SPbNIIVS is approved for use for specific prophylaxis of influenza in children aged 6 to 17 years in the Russian Federation, the Republic of Belarus, Latin America and the Caribbean.The trial is registered at ClinicalTrials. gov (NCT 05317767).

Oral prolonged-release ketamine in treatment-resistant depression - A double-blind randomized placebo-controlled multicentre trial of KET01, a novel ketamine formulation – Clinical and safety results

IntroductionWe investigated the antidepressant effects of a novel oral prolonged-release formulation of racemic ketamine (KET01) in patients suffering from treatment-resistant depression (TRD) as add-on therapy. Material and methodsPatients were randomized to an additional 160 mg/day or 240 mg/day KET01 or placebo for 14 days. The primary endpoint was change in Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline to day 15. For treatment group comparisons, we used ANOVA with pairwise least squares mean difference tests in a mixed model repeated measures analysis. ResultsTwenty-seven patients completed the double-blind protocol before trial premature termination due to poor recruitment during the COVID-19 pandemic. Mean (SD) MADRS scores on day 15 were 23 (10.32) in placebo, 25 (8.28) with 160 mg/day and 17 (10.32) with 240 mg/day KET01. MADRS change was numerically larger but statistically non-significant in the 240 mg/day KET01 group vs placebo on day 7 (−5.67; p = 00.106) and day 15 was (difference: 4.99; p = 00.15). In exploratory analysis, baseline leukocyte count correlated with response to KET01 (p = 00.01).Distribution of adverse event rates were comparable between the treatment arms. Safety analysis did not identify increased risk of suicidality, dissociation, hear rate, systolic and diastolic blood pressure associated with trial treatment. DiscussionOur results suggest that adjunctive oral administration of prolonged-release ketamine at a dose of 240 mg/day shows a positive, although statistically non-significant, trend towards antidepressant efficacy, however, the benefit could not be confirmed due to premature trial termination. Given its ease of use and low side effects, further trials are warranted to investigate this route of ketamine administration as a promising potential treatment of TRD.

Home-based Intervention with Semaglutide Treatment of Neuroleptic-Related Prediabetes (HISTORI): protocol describing a prospective, randomised, placebo controlled and double-blinded multicentre trial

IntroductionSubjects with schizophrenia have a 2–3 fold higher mortality rate than the general population and a reduced life expectancy of 10–20 years. Approximately one-third of this excess mortality has been...

Targeting histamine receptor 4 in cholinergic urticaria with izuforant (LEO 152020): results from a phase IIa randomized double-blind placebo-controlled multicentre crossover trial.

Cholinergic urticaria (CholU) is a common subtype of chronic inducible urticaria, where signs and symptoms (e.g. pruritic wheals and angioedema) are triggered by sweating due to physical exercise, passive warming and by other sweat-inducing situations. While guidelines recommend treatment with second-generation H1 antihistamines, approximately 90% of patients report uncontrolled disease. Targeting the histamine 4 receptor (H4R) has shown promise in preclinical/clinical studies of allergic/inflammatory diseases. Izuforant (LEO 152020) is a selective oral H4R antagonist with expected dual antipruritic and anti-inflammatory effects. To assess the effects of izuforant in adults with CholU, a common type of chronic urticaria driven by histamine and characterized by high skin levels of H4R expression. This was a phase IIa randomized double-blind placebo-controlled multicentre crossover trial where patients with CholU with an inadequate response to ≥ 1 standard dose of H1 antihistamine received izuforant 100 mg twice daily or placebo (EUCTR2020-004961-38-DE; NCT04853992). The primary endpoint was change from baseline in Urticaria Activity Score. Exploratory endpoints included CholU activity score over 7 days, urticaria control test, Physician Global Assessment, patient global assessment of severity (PGA-S), provocation tests, Dermatology Life Quality Index and CholU quality of life (CholU-QoL). Pharmacokinetic and pharmacodynamic parameters, and serum biomarkers were assessed, as well as safety and tolerability. Nineteen patients were randomized and included in the full analysis set; 18 completed treatment [mean (SD) age 29.5 (9.8) years; mean (SD) CholU duration 8.0 (6.3) years]. The primary and most of prespecified exploratory endpoints were not met; there were significant improvements in PGA-S for izuforant vs. placebo (P = 0.02), and nonsignificant improvements for other endpoints in quality of life and histamine skin prick test. All adverse events (AEs) experienced with izuforant were considered mild. The most frequently reported (> 1 patient) were nausea (three patients) and upper abdominal pain (two patients), occurring more frequently with izuforant vs. placebo (one patient each). There were no treatment-related serious AEs and no patient receiving izuforant discontinued the study. Treatment with izuforant did not cause downregulation of H4R. This is the first study to explore the role of H4R as a therapeutic target in urticaria. Targeting H4R with izuforant was well tolerated but did not demonstrate significant improvements vs. placebo in the primary endpoint and all but one prespecified exploratory endpoint in CholU.

Association of Glutamate Infusion With Risk of Acute Kidney Injury After Coronary Artery Bypass Surgery

Acute kidney injury (AKI) after cardiac surgery is associated with increased morbidity and mortality, and measures to prevent AKI have had limited success. Glutamate has been reported to enhance natural postischemic recovery of the heart, but not among animals and humans with diabetes. To summarize pooled results from the GLUTAMICS (Glutamate for Metabolic Intervention in Coronary Surgery) trials regarding the effect of glutamate on postoperative AKI among patients without diabetes undergoing coronary artery bypass graft (CABG) surgery. Data on a total of 791 patients without diabetes from 2 prospective, randomized, double-blind multicenter trials performed at 5 cardiac surgery centers in Sweden between October 4, 2005, and November 12, 2009, and between November 15, 2015, and September 30, 2020, were pooled. Patients had acute coronary syndrome, left ventricular ejection fraction of 0.30 or less, or a European System for Cardiac Risk Evaluation II score of 3.0 or more and underwent CABG with or without additional valve procedure. Statistical analysis was performed from May to November 2023. Intravenous infusion of 0.125-M l-glutamic acid or saline at 1.65 mL/kg/h for 2 hours during reperfusion, after which the infusion rate was halved and an additional 50 mL was given. The primary end point was AKI, defined as postoperative increase of plasma creatinine of 50% or more, corresponding to the Risk stage or higher in the Risk, Injury, Failure, Loss, and End-Stage kidney disease (RIFLE) criteria. A total of 791 patients without diabetes (391 who received glutamate [mean (SD) age, 69.3 (9.1) years; 62 women (15.9%)] and 400 controls [mean (SD) age, 69.6 (9.5) years; 73 women (18.3%)]) were randomized. Baseline data did not differ between groups. Glutamate was associated with a significantly lower risk of AKI (relative risk, 0.49 [95% CI, 0.29-0.83]). Dialysis was required for 2 patients in the glutamate group and 5 patients in the control group. In multivariable analysis, glutamate remained significantly associated with a protective effect against AKI (odds ratio, 0.47 [95% CI, 0.26-0.86]). In the glutamate and control groups, the rate of postoperative mortality at 30 days or less was 0.5% (2 of 391) vs 1.0% (4 of 400), and the rate of stroke at 24 hours or less was 0.8% (3 of 391) vs 1.8% (7 of 400). In this pooled analysis of 2 randomized clinical trials, infusion of glutamate was associated with a markedly lower risk of AKI after CABG among patients without diabetes. The findings are exploratory and need to be confirmed in prospective trials. ClinicalTrials.gov Identifiers: NCT00489827 and NCT02592824.

N-Acetylcysteine and a Specialized Preventive Intervention for Individuals at High Risk for Psychosis: A Randomized Double-Blind Multicenter Trial

Abstract Background and Hypothesis Clinical high risk for psychosis (CHR-P) offers a window of opportunity for early intervention and recent trials have shown promising results for the use of N-acetylcysteine (NAC) in schizophrenia. Moreover, integrated preventive psychological intervention (IPPI), applies social-cognitive remediation to aid in preventing the transition to the psychosis of CHR-P patients. Study Design In this double-blind, randomized, controlled multicenter trial, a 2 × 2 factorial design was applied to investigate the effects of NAC compared to placebo (PLC) and IPPI compared to psychological stress management (PSM). The primary endpoint was the transition to psychosis or deterioration of CHR-P symptoms after 18 months. Study Results While insufficient recruitment led to early trial termination, a total of 48 participants were included in the study. Patients receiving NAC showed numerically higher estimates of event-free survival probability (IPPI + NAC: 72.7 ± 13.4%, PSM + NAC: 72.7 ± 13.4%) as compared to patients receiving PLC (IPPI + PLC: 56.1 ± 15.3%, PSM + PLC: 39.0 ± 17.4%). However, a log-rank chi-square test in Kaplan–Meier analysis revealed no significant difference of survival probability for NAC vs control (point hazard ratio: 0.879, 95% CI 0.281–2.756) or IPPI vs control (point hazard ratio: 0.827, 95% CI 0.295–2.314). The number of adverse events (AE) did not differ significantly between the four groups. Conclusions The superiority of NAC or IPPI in preventing psychosis in patients with CHR-P compared to controls could not be statistically validated in this trial. However, results indicate a consistent pattern that warrants further testing of NAC as a promising and well-tolerated intervention for CHR patients in future trials with adequate statistical power.

The effect of postoperative intravenous iron in anaemic, older cardiac surgery patients on disability-free survival (AGE ANEMIA study): study protocol for a multi-centre, double-blind, randomized, placebo-controlled trial

BackgroundPostoperative anaemia is common in older cardiac surgery patients and often caused by iron deficiency. Anaemia may negatively affect recovery after cardiac surgery. This study aims to determine the efficacy of treatment of postoperative iron deficiency anaemia (IDA) with intravenous iron (IVI) on disability 90 days after cardiac surgery in older patients.MethodsThis is a randomized placebo-controlled double-blind multi-centre trial. In total, 310 patients aged ≥ 70 years with moderate IDA on postoperative day 1 (haemoglobin 85–110 g/L and ferritin concentration < 100 μg/L or iron saturation < 20%) after uncomplicated elective cardiac surgery (aortic valve repair or coronary artery bypass graft surgery) will be included. Patients will be randomly allocated to receive either IVI (ferric derisomaltose) or placebo (sodium chloride 0.9%) on postoperative day 1 in a 1:1 ratio, stratified by centre and type of cardiac surgery. The primary outcome is disability measured by the 12-item World Health Organization Disability Assessment score 2.0 after 90 days. Secondary outcome measures are the number of postoperative red blood cell (RBC) transfusions, change in reticulocyte haemoglobin content (pg) from randomization to hospital discharge, Hb levels at discharge, hospital complications, dyspnoea (assessed with the Rose Dyspnoea Scale) and health-related quality of life (HRQL) (assessed with The Older Persons and Informal Caregivers-Short Form (TOPICS-SF) questionnaire) after 90 days and days alive and out of hospital after 90 days. Lastly, the functional outcomes (e.g. steep ramp or 6-min walk test) and Hb level after 90 days will be assessed as an exploratory endpoint.DiscussionThe results of this study will demonstrate whether early treatment of postoperative IDA with IVI improves disability at 90 days in older cardiac surgery patients.Trial registrationClinicalTrials.gov NCT04913649. Registered on June 4, 2021.

Efficacy and Safety of Chinese Herbal Medicine in Patients with Acute Intracerebral Hemorrhage: Protocol for a Randomized Placebo-Controlled Double-Blinded Multicenter Trial

Introduction: The popular traditional Chinese medicine (TCM) compound FYTF-919 (Zhong Feng Xing Nao prescription) may improve outcome from acute intracerebral hemorrhage (ICH) through effects on brain edema, hematoma absorption, and the immune system. This study is to assess whether FYTF-919 is safe and effective as compared to matching placebo treatment in patients with acute ICH. Methods: The ongoing Chinese Herbal medicine in patients with Acute INtracerebral hemorrhage (CHAIN) is a multicenter, prospective, randomized, double-blind placebo-controlled trial of FYTF-919 in patients with acute ICH at 20–30 hospital sites in China. Eligible ICH patients presenting within 48 h after symptom onset are randomly allocated to receive either FYTF-919 (100 mL per day × 28 d, oral) or matching placebo. A sample size of 1,504 patients is estimated to provide 90% power (α 0.05) to detect a ≥20% improvement in average utility-weight scores on the modified Rankin scale (UW-mRS) assessed at 90 days, with 6% non-adherence and 10% lost to follow-up. The primary efficacy outcome is UW-mRS at 90 days. Secondary outcomes include binary measures of the mRS, neurological impairment on the National Institute of Health Stroke Scale, and health-related quality of life on the EuroQol EQ-5D-5L scale at different time points over 6 months of follow-up. The key safety measure is serious adverse events. Conclusion: CHAIN is on schedule to provide reliable evidence over the benefits of a popular herbal TCM for the treatment of acute ICH.

Glutamate Infusion Reduces Myocardial Dysfunction after Coronary Artery Bypass Grafting According to NT-proBNP: Summary of 2 Randomized Controlled Trials (GLUTAmate for Metabolic Intervention in Coronary Surgery [GLUTAMICS I-II

BackgroundGlutamate is reported to enhance the recovery of oxidative metabolism and contractile function of the heart after ischemia. The effect appears to be blunted in diabetic hearts. Elevated plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) reflects myocardial dysfunction. In the GLUTAmate for Metabolic Intervention in Coronary Surgery (GLUTAMICS) II trial, the proportion of patients with diabetes had nearly doubled to 47% compared with the cohort used for sample size estimation, and a significant effect on the postoperative rise in NT-proBNP was only observed in patients without diabetes. ObjectiveWe aimed to summarize the pooled NT-proBNP results from both GLUTAMICS trials and address the impact of diabetes. MethodsData from 2 prospective, randomized, double-blind multicenter trials with similar inclusion criteria and endpoints were pooled. Patients underwent a coronary artery bypass grafting (CABG) ± valve procedure and had a left-ventricular ejection fraction of ≤0.30 or a European System for Cardiac Operative Risk Evaluation II (EuroSCORE II) of ≥3.0 with at least 1 cardiac risk factor. Intravenous infusion of 0.125 M L-glutamic acid or saline at 1.65 mL/kg/h was started 10–20 min before reperfusion and continued for 150 min. The primary endpoint was the difference between preoperative and day 3 postoperative NT-proBNP levels. ResultsA total of 451 patients, 224 receiving glutamate and 227 controls, fulfilled the inclusion criteria. Glutamate was associated with a reduced primary endpoint (5344 ± 5104 ng/L and 6662 ± 5606 ng/L in glutamate and control groups, respectively; P = 0.01). Postoperative mortality at ≤30 d was 0.9% and 3.5% (P = 0.11), whereas stroke at ≤24 h was 0.4% and 2.6% in glutamate and control groups, respectively (P = 0.12). No adverse events related to glutamate were observed. A significant interaction regarding the primary endpoint was only detected between glutamate and insulin-treated diabetes groups (P = 0.04). Among patients without insulin-treated diabetes, the primary endpoint was 5047 ± 4705 ng/L and 7001 ± 5830 ng/L in the glutamate and control groups, respectively (P = 0.001). ConclusionsInfusion of glutamate reduced the postoperative rise in NT-proBNP after CABG in medium- to high-risk patients. A significantly blunted effect was observed only in insulin-treated patients with diabetes. Clinical trial detailsThis trial was registered at www.clinicaltrials.gov as NCT02592824.

A multicenter, randomized, placebo-controlled phase IIb trial of an autologous formalin-fixed tumor vaccine for newly diagnosed glioblastomas.

An autologous formalin-fixed tumor vaccine (AFTV) derived from resected glioblastoma (GBM) tissue can be used against unidentified tumor antigens. Thus, the authors conducted a multicenter double-blind phase IIb trial to investigate the efficacy of an AFTV. Eligible patients were adults with supratentorial GBMs, 16-75 years of age, with Karnofsky Performance Scale (KPS) scores ≥ 60%, and no long-term steroid administration. An AFTV comprising fixed paraffin-embedded tumor tissue with immune adjuvants or an identical placebo without fixed tumor tissue was injected intradermally over three courses before and after chemoradiotherapy. The primary and secondary end points were overall survival (OS), progression-free survival (PFS), and 3-year survival rate. Sixty-three patients were enrolled. The average patient age was 61 years. The median KPS score was 80%, and the median resection rate was 95%. The full analysis set of 57 patients indicated no significant difference in OS (p = 0.64) for the AFTV group (median OS 25.6 months, 3-year OS rate 38%) compared with the placebo group (31.5 months and 41%, respectively) and no difference in PFS (median PFS 13.3 months in both groups, p = 0.98). For patients with imaging-based total tumor removal, the 3-year PFS rate was 81% in the AFTV group versus 46% in the placebo group (p = 0.067), whereas the 3-year OS rate was 80% versus 54% (p = 0.16), respectively. Similar results were obtained in the p53-negative subgroups. Severe adverse effects were not observed. The AFTV may have potential effects in certain patient subgroups. A phase III study for patients with total tumor removal remains warranted to confirm these findings. Clinical trial registration no.: UMIN000010602 (UMIN Clinical Trials Registry).

Low dose of liraglutide combined with metformin leads to a significant weight loss in Chinese Han women with polycystic ovary syndrome: a retrospective study

Background Polycystic ovary syndrome (PCOS) is the most common endocrine disorder with complex pathophysiological mechanism. It is reported that even a modest weight loss of 5–10% substantially may improve the reproductive and metabolic profile. This study aims to assess the efficacy of the low dose of liraglutide (0.6 mg QD) combined with metformin (0.85 mg BID) in weight loss in Chinese Han women with PCOS. Methods We included clinical data of 102 obese/overweight (≥18 years, body mass index ≥28 kg/m2 or ≥24 kg/m2) women who were diagnosed with PCOS from October 2016 to March 2018 in Wuhan Union Hospital initially. They were treated with dinae-35, low dose of liraglutide (0.6 mg QD) and metformin (0.85 mg BID) for 12 weeks. The demographic and clinical data were retrieved retrospectively, and weight loss was the main outcome measure. Student’s paired t-test and Wilcoxon rank sum test were used to compare the differences before and after therapy, p < 0.05 was considered statistically significant. Results Participants(n = 102)had lost a mean of 7.20 ± 3.42 kg of body weight (95%CI: 6.55–7.86, p < 0.001), and the mean reduction of BMI was 2.87 ± 1.36 kg/m2 (95%CI: 0.02–0.27, p < 0.001). A total of 88.24% of participants lost more than 5% of their body weight. Conclusion The combination of low dose of liraglutide and metformin was associated with significant reduction of body weight in Chinese Han women with PCOS. Additionally, a larger randomized double-blind multicenter controlled clinical trial is needed to confirm that. Trial registration The study was registered on http://www.chictr.org.cn as ChiCTR1900024384.

Efficacy and safety of Y-2 sublingual tablet for patients with acute ischaemic stroke: protocol of a phase III randomised double-blind placebo-controlled multicentre trial

Background and purposeClinical studies have demonstrated that edaravone dexborneol can improve the functional outcomes in patients with acute ischaemic stroke (AIS). The present clinical trial aimed at testing the efficacy...

Which trial do we need? Mannitol therapy in hospitalized adult patients with tick-borne encephalitis and brain oedema: a double-blind placebo-controlled multicentre randomized trial

Tick-borne encephalitis (TBE) is an infection of the central nervous system (CNS) caused by tick-borne encephalitis virus (TBEV) [ 1 Mickiené A. Laiškonis A. Günther G. Vene S. Å Lundkvist Lindquist L. Tickborne encephalitis in an area of high endemicity in Lithuania: Disease severity and long-term prognosis. Clinical Infectious Diseases. 2002; 35: 650-658https://doi.org/10.1086/342059 Crossref PubMed Scopus (179) Google Scholar , 2 Ruzek D. Avšič Županc T. Borde J. Chrdle A. Eyer L. Karganova G. et al. Tick-borne encephalitis in Europe and Russia: Review of pathogenesis, clinical features, therapy, and vaccines. Antiviral Res. 2019; 164: 23-51https://doi.org/10.1016/j.antiviral.2019.01.014 Crossref PubMed Scopus (173) Google Scholar ]. In 2020, there were 3734 confirmed cases of TBE in Europe (Russian Federation excluded) and Slovenia had one of the highest incidence rates with 8.9 confirmed TBE cases per 100,000 population [ 3 ECDC. Tick-borne encephalitis: Annual Epidemiological Report for 2020. Stockholm; 2020. Google Scholar ]. The virus is transmitted to humans principally through tick bites. There are three known subtypes of TBEV: European (EU-TBEV), Siberian and Far Eastern. Of all three subtypes, EU-TBEV causes the mildest disease [ 1 Mickiené A. Laiškonis A. Günther G. Vene S. Å Lundkvist Lindquist L. Tickborne encephalitis in an area of high endemicity in Lithuania: Disease severity and long-term prognosis. Clinical Infectious Diseases. 2002; 35: 650-658https://doi.org/10.1086/342059 Crossref PubMed Scopus (179) Google Scholar , 2 Ruzek D. Avšič Županc T. Borde J. Chrdle A. Eyer L. Karganova G. et al. Tick-borne encephalitis in Europe and Russia: Review of pathogenesis, clinical features, therapy, and vaccines. Antiviral Res. 2019; 164: 23-51https://doi.org/10.1016/j.antiviral.2019.01.014 Crossref PubMed Scopus (173) Google Scholar ]. The majority of infections caused by EU-TBEV are asymptomatic (70-90%). Among symptomatic cases, approximately 40-50% develop meningitis, 50% meningoencephalitis, and 10% meningoencephalomyelitis [ 4 Kaiser R. Tick-borne encephalitis. Infect Dis Clin N Am. 2008; 22: 561-575https://doi.org/10.1016/j.idc.2008.03.013 Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar ]. The case-fatality rate in EU-TBE ranges from 0.5 to 2%, whereas 30‒46% of patients report incomplete recovery (residual neurological deficit) manifesting as residual symptoms/signs such as headache, memory and concentration disorders, fatigue, emotional lability, coordination disorders, tremor, hearing loss/tinnitus, and flaccid paresis [ 1 Mickiené A. Laiškonis A. Günther G. Vene S. Å Lundkvist Lindquist L. Tickborne encephalitis in an area of high endemicity in Lithuania: Disease severity and long-term prognosis. Clinical Infectious Diseases. 2002; 35: 650-658https://doi.org/10.1086/342059 Crossref PubMed Scopus (179) Google Scholar , 5 Velušček M. Blagus R. Kišek T.C. Ružić-Sabljić E. Avšič-županc T. Bajrović F.F. et al. Antibiotic Use and Long-Term Outcome in Patients with Tick-Borne Encephalitis and Co-Infection with Borrelia Burgdorferi Sensu Lato in Central Europe. A Retrospective Cohort Study. J Clin Med. 2019; 8: 1740https://doi.org/10.3390/jcm8101740 Crossref Scopus (4) Google Scholar , 6 Taba P. Schmutzhard E. Forsberg P. Lutsar I. Ljøstad U. Mygland et al. EAN consensus review on prevention, diagnosis and management of tick-borne encephalitis. Eur J Neurol. 2017; 24: 1214-e61https://doi.org/10.1111/ene.13356 Crossref Scopus (115) Google Scholar , 7 Bogovič P. Stupica D. Rojko T. Lotrič-Furlan S. Avšič-Županc T. Kastrin A. et al. The long-term outcome of tick-borne encephalitis in Central Europe. Ticks Tick Borne Dis. 2018; 9: 369-378https://doi.org/10.1016/j.ttbdis.2017.12.001 Crossref Scopus (35) Google Scholar ]. These symptoms/signs decline over time and their frequency stabilises 12 months after the acute illness [ 7 Bogovič P. Stupica D. Rojko T. Lotrič-Furlan S. Avšič-Županc T. Kastrin A. et al. The long-term outcome of tick-borne encephalitis in Central Europe. Ticks Tick Borne Dis. 2018; 9: 369-378https://doi.org/10.1016/j.ttbdis.2017.12.001 Crossref Scopus (35) Google Scholar ].

Melatonin as a Chronobiotic/Cytoprotective Agent in REM Sleep Behavior Disorder.

Dream-enactment behavior that emerges during episodes of rapid eye movement (REM) sleep without muscle atonia is a parasomnia known as REM sleep behavior disorder (RBD). RBD constitutes a prodromal marker of α-synucleinopathies and serves as one of the best biomarkers available to predict diseases such as Parkinson disease, multiple system atrophy and dementia with Lewy bodies. Most patients showing RBD will convert to an α-synucleinopathy about 10 years after diagnosis. The diagnostic advantage of RBD relies on the prolonged prodromal time, its predictive power and the absence of disease-related treatments that could act as confounders. Therefore, patients with RBD are candidates for neuroprotection trials that delay or prevent conversion to a pathology with abnormal α-synuclein metabolism. The administration of melatonin in doses exhibiting a chronobiotic/hypnotic effect (less than 10 mg daily) is commonly used as a first line treatment (together with clonazepam) of RBD. At a higher dose, melatonin may also be an effective cytoprotector to halt α-synucleinopathy progression. However, allometric conversion doses derived from animal studies (in the 100 mg/day range) are rarely employed clinically regardless of the demonstrated absence of toxicity of melatonin in phase 1 pharmacological studies with doses up to 100 mg in normal volunteers. This review discusses the application of melatonin in RBD: (a) as a symptomatic treatment in RBD; (b) as a possible disease-modifying treatment in α-synucleinopathies. To what degree melatonin has therapeutic efficacy in the prevention of α-synucleinopathies awaits further investigation, in particular multicenter double-blind trials.

Randomised Double-blind Placebo-Controlled Multicentre Trial for the Effects of Yokukansan in Smokers with Depressive Tendencies.

Randomised Double-blind Placebo-Controlled Multicentre Trial for the Effects of Yokukansan in Smokers with Depressive Tendencies.

The Effect of Sacubitril/Valsartan on Left Ventricular Myocardial Deformation in Heart Failure with Preserved Ejection Fraction (PARAMOUNT trial)

BackgroundGlobal longitudinal strain (GLS) and global circumferential strain (GCS) have been shown to be impaired in heart failure with preserved ejection fraction. We sought to assess whether treating patients with heart failure with preserved ejection fraction with sacubitril/valsartan would significantly improve GLS and GCS compared with valsartan alone. Methods and ResultsPARAMOUNT (Prospective Comparison of ARNI With ARB on Management of Heart Failure With Preserved Ejection Fraction Trial) was a phase II, randomized, parallel-group, double-blind multicenter trial in 301 patients with New York Heart Association functional class II–III heart failure, a left ventricular ejection fraction of 45%, and an N-terminal pro-B-type natriuretic peptide of ≥400 pg/mL. Participants were randomly assigned (1:1) to sacubitril/valsartan titrated to 200 mg twice daily or valsartan titrated to 160 mg twice daily for 36 weeks. We assessed changes in the GLS and the GCS from baseline to 36 weeks, adjusting for baseline value, in patients with sufficient imaging quality for 2-dimensitonal speckle tracking analysis at both timepoints (n = 60 sacubitril/valsartan, n = 75 valsartan only). GCS was significantly improved at 36 weeks in the sacubitril/valsartan group when compared with the valsartan group (Δ4.42%, 95% confidence interval [CI] 0.67–8.17, P = .021), with no significant difference observed in GLS (Δ0.25%, 95% CI, –1.19 to 1.70, P = .73). Patients with a history of hospitalization for heart failure had a differentially greater improvement in GCS when treated with sacubitril/valsartan. ConclusionsIn patients with heart failure with preserved ejection fraction, sacubitril/valsartan improved GCS but not GLS when compared with valsartan during a 36-week period. This trial is registered at ClinicalTrials.gov, NCT00887588.