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On September 18, 2007, a collaborative session between the International Society for CNS Clinical Trials and Methodology and the International Society for CNS Drug Development was held in Brussels, Belgium. Both groups, with membership from industry, academia, and governmental and nongovernmental agencies, have been formed to address scientific, clinical, regulatory, and methodological challenges in the development of central nervous system therapeutic agents. The focus of this joint session was the apparent diminution of drug-placebo differences in recent multicenter trials of antipsychotic medications for schizophrenia. To characterize the nature of the problem, some presenters reported data from several recent trials that indicated higher rates of placebo response and lower rates of drug response (even to previously established, comparator drugs), when compared with earlier trials. As a means to identify the possible causes of the problem, discussions covered a range of methodological factors such as participant characteristics, trial designs, site characteristics, clinical setting (inpatient vs outpatient), inclusion/exclusion criteria, and diagnostic specificity. Finally, possible solutions were discussed, such as improving precision of participant selection criteria, improving assessment instruments and/or assessment methodology to increase reliability of outcome measures, innovative methods to encourage greater subject adherence and investigator involvement, improved rater training and accountability metrics at clinical sites to increase quality assurance, and advanced methods of pharmacokinetic/pharmacodynamic modeling to optimize dosing prior to initiating large phase 3 trials. The session closed with a roundtable discussion and recommendations for data sharing to further explore potential causes and viable solutions to be applied in future trials.

Author(s): Pankaj Kumar [1]; Sanjeev Kumar [1]; Mumtaz Hussain [1]; Ritu Singh [1]; Waquas Ahmed [1]; Ravi Anand [2] INTRODUCTION Critically ill patients often receive tracheostomy for long-term ventilatory support. [...], Background and Aiims Percutaneous dilational tracheostomy (PDT) is a common procedure in intensive care unit (ICU) patients requiring long-term mechanical ventilation. PDT has gradually replaced surgical tracheostomy because it is associated with minimal invasiveness, reduced bleeding and simplicity in technique.This study was conducted to compare ultrasound-guided PDT versus conventional tracheostomy in terms of duration of the procedure, number of passes and immediate peri-procedural complications. Methods A total of 72 patients with clinical indications of tracheostomy were recruited. A total of 12 patients met the exclusion criteria. The remaining were randomly assigned into two groups of 30 each: Group A (Landmark) with traditional anatomical landmark and Group B (USG) with real-time ultrasound guidance. Puncture positions were recorded with bronchoscopy. Midline deviation was captured on a bronchoscopy image using a protractor. Data on procedural safety and efficacy were also collected. Results : Group B had significantly fewer cases of midline deviation (11.33 ± 9.51) in comparison to Group A (16.60 ± 12.31). Trials > 2 were equal to 11 in Group A and 2 in Group B. However, the duration of the procedure was higher in Group B (20.07 ± 3.25 min) as compared to Group A (15.20 ± 3.71 min). Peri-procedural and post-procedural complications were also higher in the Landmark group. Conclusion : Ultrasound-guided PDT showed superiority over landmark PDT in terms of less number of trials, midline puncture and fewer complications. However, it took a little longer to perform USG-guided PDT. Keywords: Key words: Critical illness, tracheostomy, ultrasound

Globe rupture in children usually occurs from injury with sharp objects. Our patient had a pungai (Indian beech tree) seed thrown at his right eye and presented with ruptured globe. Globe repair was done, and the patient had a good visual outcome. Awareness about the outcome of open globe injury with unusual things should be created.

Background: Despite over 5 decades of availability of antipsychotics (APs), 30-60% of patients with schizophrenia show no, and another 10 30% show inadequate, benefit from APs [1,2], resulting in increased risk for hospitalization, morbidity, suicidality, and reduced lifespan [3,4]. Increasing evidence supports an important role of the glutamatergic neurotransmitter system, which is not targeted by 5HT2/D2-blocking APs [5,6,7]. Evenamide is a selective inhibitor of voltage-gated sodium channels, devoid of effects at more than130 CNS targets [8]. It reduces aberrant neuronal firing, normalizing excessive glutamate release without any effect on basal glutamate. Data from animal models of psychosis indicate the combination of ineffective doses of APs and evenamide was associated with significant benefit, suggesting synergistic mechanisms that would benefit patients with inadequate response to current APs. Preliminary evidence of efficacy of evenamide added on to an AP was demonstrated in two phase II trials, one placebocontrolled in non-TRS [9], the other open-label, long-term in TRS patients [10]. Aims & Objectives: This phase 2/3, potentially pivotal, international, randomized, double-blind, placebo-controlled, 4-week study was designed to assess the efficacy and safety of evenamide 30 mg bid added on to an atypical AP (including clozapine) in patients with schizophrenia not responding adequately to their current AP. Method: Eligible patients must have a diagnosis of schizophrenia (DSM-5) and be symptomatic despite treatment with an atypical AP for an adequate period at a therapeutic dose. Adherence to the current AP was assessed through determination of blood levels. At baseline, patients were moderately to severely ill (CGI-S 4-6), with a PANSS total score of 70-85 and predominant positive symptoms (PANSS positive total score equal or more than 20). Changes from baseline to endpoint (Day 29) for the key efficacy outcome measures (PANSS, CGI-S, LOF, MSQ) will be compared between evenamide and placebo groups using a Mixed Model Repeated Measures (MMRM) analysis. Proportions of patients improving on the CGI-C, as well as meeting other responder criteria, will be compared between groups using a logistic regression model (chi-square test). Results: To date ~235 patients have been randomized, with a very low dropout rate (~2.5%) and high compliance to the study medication, suggesting that evenamide is well tolerated. Routine interim safety analyses reviewed by the ISMB did not detect any evidence of toxicity. Patients' mean age is ~40 years, ~75% are males, with a mean PANSS total score of 78, and mean duration of illness of ~11 years. The most common background APs are risperidone (~40%), olanzapine (~20%), and clozapine (~15%); mean duration of treatment with current AP is >1-year. Although the protocol excluded patients with TRS, many patients (55%) had already failed at least 2 trials with different APs. Final efficacy and safety results will be available by the time of the Congress. Discussion & Conclusions: Study 008A represents the first placebocontrolled, double-blind trial of evenamide 30 mg bid as add-on to an AP in patients with schizophrenia. If positive, these results may change the treatment paradigm of patients with chronic schizophrenia, confirming the benefit of evenamide in patients with schizophrenia on an AP. [ABSTRACT FROM AUTHOR]

Background: TRS affects 30% of patients with schizophrenia, resulting in higher rates of hospitalization, morbidity, suicidality, and mortality [1,2]. Clozapine, the only drug approved for TRS, is vastly under-utilized, due to its severe sideeffects and blood monitoring requirement, and >30% of patients do not respond to clozapine. Other strategies to treat TRS such as high doses of antipsychotics (APs), or AP polypharmacy, are not shown to be effective [3,4,5]. Findings from neurochemistry, neuroimaging and neurometabolism studies of TRS patients indicate abnormalities in the glutamatergic neurotransmission, rather than excess of dopamine synthesis, that lead to failure to respond to current 5HT/D2 antipsychotics.[6] Evenamide, an orally available new chemical entity, is a voltage-gated sodium channel blocker, with no biological activity at >130 CNS targets and normalizes glutamate release induced by aberrant sodium channel activity, without affecting basal glutamate levels. The combination of ineffective doses of evenamide and 5HT2/D2 blocking APs was associated with benefit in animal models of psychosis, suggesting synergies in mechanisms that may benefit poor responders to current APs, including clozapine.[7] Preliminary evidence of efficacy of evenamide in TRS patients has been shown in a pilot, phase 2, open-label, rater-blinded, 1-year study, where increasing benefits were noted across all efficacy measures over time. Clinically important increases in responder rates were noted for the key efficacy measures (PANSS, CGI-S, and CGI-C).[8] Aims & Objectives: A prospective, potentially pivotal, phase 3, randomized, double-blind, placebo-controlled, 1-year, international study will be performed to demonstrate the efficacy and tolerability of two doses (15 and 30 mg bid) of evenamide as add-on therapy in TRS patients not benefiting from their' standard of care' treatment with APs (including clozapine). Methods: This study will enrol >450 adult schizophrenia patients meeting the TRRIP criteria [9], requiring a history of failure on at least 2 APs (2 different chemical classes; at least one secondgeneration AP) for an adequate period, including a 6-week prospective failure. Selection criteria include schizophrenia diagnosis (DSM V), CGI-S score 3-6; BPRS total score >45, with a score >=18 on positive symptoms of psychosis. Patients will be enrolled based on acceptability of their screening data by an Independent Eligibility Committee. Patients improving >=20% on the BPRS or >=1 category on the CGI-S during the 6-week screening period will be excluded. Adherence to the background AP and study medication will be confirmed by measurement of plasma levels. Efficacy and safety will be evaluated regularly, with Weeks 12 and 26 as efficacy endpoints; the study will continue under blinded conditions up to Week-52. Efficacy Measures Include: PANSS total (primary), CGI-S (key secondary), CGI-C, Q-LES-Q-SF and PSP scales, assessment of cognition and pharmacoeconomic outcomes. Safety measurements include vital signs, ECG, laboratory tests, physical/neurological/eye examinations, ASEX, ESRS-A, CDSS, and C-SSRS. Results: The results of the study will demonstrate if addition of evenamide to patients with TRS on APs is associated with efficacy and tolerability. Discussion & Conclusions: Results from this study will determine if glutamate modulation by evenamide may represent a new therapeutic strategy for the treatment of patients with TRS. [ABSTRACT FROM AUTHOR]

Background: Numerous findings indicate reduced life-expectancy in patients with TRS, along with multiple morbidities, frequent hospitalizations, indigent status, and increasing costs of care for families and society [1]; no new treatment has emerged since clozapine approval in 1989 [2]. Despite its therapeutic promise, current experience indicates that less than 5% and 15% of TRS patients in the US, and in the EU respectively, receive clozapine [Global Data; 2017]. The vast majority of TRS patients are managed by off-label use of first and second-generation antipsychotics (APs) in conjunction with other psychopharmaceuticals, without showing efficacy [3]. Evenamide, a selective inhibitor of voltage-gated sodium channels, devoid of biological activity at >130 CNS targets, normalizes glutamate release [4,5,6,7] without affecting its basal levels. Preclinical experiments have indicated that it is likely to benefit patients responding inadequately or resistant to APs. Evenamide was evaluated as monotherapy or add-on to APs in animal models in which PPI was impaired using amphetamine, scopolamine, phencyclidine, MK-801, ketamine, or sleep deprivation. It demonstrated efficacy across a broad spectrum of experiments, including models of mania, depression, impulse control loss, and obsessive-compulsive behavior. Aims & Objectives: To present final, 1-year results of evenamide treatment in TRS patients unstable on their current AP. This data will demonstrate the unique benefits of glutamate modulation, when added to 5HT2/D2 modulators. It is likely that profound long-lasting efficacy of the combination, observed in shorter trials, will be demonstrated on efficacy variables used to assess patients with schizophrenia, as well as on key characteristics of TRS patients. Methods: The selection criteria for the study require patients to meet standardized criteria for TRS: non-response to two APs, baseline PANSS total score 70-90 with predominant positive symptoms, at least two moderate core symptoms and functional deficits. Efficacy data (PANSS, CGI-S/C, and LOF) were analyzed using paired t-test to assess changes from baseline to endpoint (1-year) for each dose group and provide descriptive statistics for the responder analyses. Results: The high retention rate [82.5% after 6-month] and the low incidence of adverse dropouts [1.9%] indicate the good tolerability of evenamide. Interim analyses at 6-month (mITT=156) and 1-year for the first cohort of 100 patients, indicated that a large proportion of patients improve to an extent that they no longer meet the operational severity criteria for TRS; and a significant proportion can be considered 'responders' based on TRRIP definition (>=20% improvement on PANSS maintained for >=12 weeks [8]). Comparison of results available after 6-week, 6-month, and 1-year are likely to indicate a pattern of unique efficacy over time. Furthermore, increasing and long-lasting improvement was observed in all efficacy scales [9,10], with the largest improvement in the 15 and 30 mg bid dose groups. Full, 1-year results, available by the time of the Congress, will be presented demonstrating remarkable efficacy of evenamide at 1-year in TRS patients. Discussion: This is the first international trial of evenamide add-on to any AP (except clozapine) in patients with TRS. Encouraging results of this study have expedited the conduct of a potentially pivotal, randomized, double-blind, placebo-controlled, 1-year, international study. [ABSTRACT FROM AUTHOR]

Introduction: First-and-second-generation antipsychotics (APs) are widely used in patients with treatment-resistant schizophrenia (TRS), alone or in combination with other 5-HT2/D2-blocking APs, although AP polypharmacy shows no evidence of benefit [1]. In addition, the long-term usage of APs requires frequent dose adjustments due to development of intolerance and relapses [2], representing a major burden for patients, caregivers, and healthcare providers. TRS develops in ~30% of patients within 5 years of treatment, resulting in increased morbidity, suicidality, and mortality. Findings from neurochemistry, neurometabolism, and functional imaging studies in TRS patients indicate abnormalities in glutamatergic rather than dopaminergic neurotransmission [3, 4, 5]. Evenamide, a selective inhibitor of voltage-gated sodium channels, is devoid of biological activity at >130 CNS targets, normalizes glutamate release without affecting basal levels, and demonstrated benefits in animal models of psychosis as monotherapy and as an add on to APs. Aim & Objectives: Studies 014/015 were designed to evaluate the safety and preliminary efficacy of evenamide given orally at 3 fixed doses (7.5, 15 and 30 mg bid) in patients with TRS not responding to a therapeutic dose of an AP (except clozapine). Assessment of efficacy was based on changes of PANSSCGI-S/C and functioning (Strauss-Carpenter LOF), while tolerability was assessed based on all safety measures. Methods: Study 014 is a 6-week, randomized, open-label, raterblinded, international study with completers continuing assigned doses for an additional 46 weeks in an ongoing extension study (Study 015). At baseline, patients were moderately to severely ill (CGI-S of 4 to 6), with a PANSS total score of 70-90 and predominant positive symptoms (PANSS positive total score >=20), along with functional deficits (GAF =<50). Efficacy ratings were performed by a trained psychiatrist blinded to the evenamide dose. Data from all 3 doses were combined into a single group and analyzed to assess the responder rate, maintenance of the response up to 6 months and conversion of TRS patients already on an AP into a responsive state, according to the operational severity selection criteria. Results: The high roll-over rate (94.4%) in Study 015 and the low incidence of treatment-emergent adverse events indicate the good tolerability of evenamide. Furthermore, 6-month efficacy results confirmed the increasing and sustained improvement in all efficacy scales as seen in the cohort of the first 100 patients randomized [6,7]. During this period, more than 65% of the patients who achieved a clinically meaningful benefit (>=20% improvement on PANSS total score) at 6-week preserved their response at 6-month. In addition, ~40% of the patients no longer met the operational severity criteria for TRS used to select patients for the study, and no relapses or clinically important worsening over 6-month were observed. Detailed results from further analyses will be presented at the Congress. Discussion: Encouraging long-term results of this study have expedited the design of a phase 3, potentially pivotal, randomized, double-blind, placebo-controlled, 1-year, international study to assess efficacy and safety of two doses (15 and 30 mg bid) of evenamide as add-on treatment in TRS patients not benefiting from their current AP. [ABSTRACT FROM AUTHOR]