Search

Hiroko Kashiwagi,1 Satoru Ikezawa,2 Tomiki Sumiyoshi,3 Atsuko Kadono,4 Kazuhiko Segawa,5 Kazuyoshi Takeda,1 Mayu Omori,1 Hisako Taguchi,1 Naotsugu Hirabayashi1 1Department of Forensic Psychiatry, 2Department of Psychiatry, 3Department of Clinical Epidemiology, Translational Medical Center, National Center Hospital of Neurology and Psychiatry, Kodaira, Tokyo, 4Saitama Psychiatric Medical Center, Kitaadatigun, Saitama, 5Department of General Medicine, National Center Hospital of Neurology and Psychiatry, Kodaira, Tokyo, Japan Abstract: We present a case of schizophrenia comorbid for tetralogy of Fallot, without chromosome 22q.11.2 deletion or duplication, treated successfully with a combination of clozapine and antiepileptic drugs. Although clozapine by itself initially triggered convulsive seizures, we continued it with co-administration of valproate and topiramate. This combined treatment did not affect cardiac function of the patient, who experienced a favorable clinical course in terms of symptomatology and functional outcomes. To our knowledge, we provide the first report on a patient with tetralogy of Fallot, in whom 22q.11.2 was not deleted and clozapine-induced seizures were observed. Keywords: schizophrenia, clozapine, tetralogy of Fallot, seizure, copy number variants

Introduction: Cognitive impairment associated with schizophrenia (CIAS) is an important unmet need as there are no effective treatments available. Iclepertin (BI 425809), a glycine transporter-1 inhibitor, has been shown to improve CIAS in Phase II trials, and Phase III trials are underway. Objectives: The ongoing CONNEX-X extension study aims to collect additional safety data relating to iclepertin treatment in patients with CIAS. Methods: CONNEX-X (NCT05211947/1346-0014) is a multinational, multicentre, open-label, single-arm extension study in patients with CIAS who completed 26 weeks of treatment (iclepertin 10 mg or placebo) in one of 3 Phase III CONNEX parent trials (NCT04846868/1346-0011, NCT04846881/1346-0012, NCT04860830/1346-0013). An estimated 1400 clinically stable outpatients will be treated (iclepertin 10 mg daily) for 1 year, irrespective of previous treatment (iclepertin/placebo). Patients are excluded if any of the following circumstances occur during the parent study and up to Visit 1 of CONNEX-X: suicidal behaviour or ideation (type 5 on the Columbia-Suicide Severity Rating Scale), diagnosis with moderate/severe substance use disorder, diagnosis other than schizophrenia (according to Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition), development of any condition preventing participation, a haemoglobin level decrease (>25% or <100g/L from baseline in parent trial) or haemoglobinopathies. The primary endpoint is the occurrence of treatment-emergent adverse events. The secondary endpoints include change from baseline (CfB) in Clinical Global Impressions-Severity (CGI-S) and CfB in haemoglobin. Further efficacy endpoints include CfB in MATRICS Consensus Cognitive Battery (MCCB) overall composite T-score, CfB in Schizophrenia Cognition Rating Scale total score and CfB in Virtual Reality Functional Capacity Assessment Tool (VRFCAT) total times. Results: Currently, 460 patients have been enrolled and randomised from the parent trials with 0% screening failures (-80% roll-over rate, 30 August 2023). Current study status, including recruitment, screening failures and data collection experiences, are presented. Conclusions: Patient enrolment rates from the CONNEX trials to the CONNEX-X open-label extension study are stable. CONNEX-X will allow the exploration of long-term safety, as well as descriptive analyses of cognitive and functional endpoints of iclepertin in the treatment of CIAS. Funding: Boehringer Ingelheim Disclosure of Interest: C. Reuteman-Fowler Employee of: Boehringer Ingelheim Pharmaceuticals, Inc., Z. Blahova Employee of: Boehringer Ingelheim RCV GmbH & Co. KG, S. Marder Consultant of: Boehringer Ingelheim Pharma GmbH, Merck, Biogen and Sunovion, S. Ikezawa Consultant of: Boehringer Ingelheim Pharma GmbH, Lundbeck, Takeda Pharma, Sumitomo Dainippon Pharma, Employee of: International University of Health and Welfare, Mita Hospital, Tokyo, Japan, P. Falkai Consultant of: Boehringer Ingelheim Pharma GmbH, Boehringer Ingelheim Pharma advisory board [ABSTRACT FROM AUTHOR]

Introduction: In a 12-week, Phase II (NCT02832037) trial, iclepertin (BI 425809), an inhibitor of glycine transporter-1, was generally well tolerated and significantly improved cognition in 509 patients with schizophrenia. Objectives: The Phase III CONNEX programme aims to confirm the efficacy, safety and tolerability of iclepertin in improving cognition and functioning across a larger cohort of patients with schizophrenia. Methods: The CONNEX programme includes 3 randomised, double-blind, placebo-controlled parallel group trials in patients with schizophrenia (NCT04846868, NCT04846881, NCT04860830) receiving stable antipsychotic treatment. Each trial aims to recruit ˜586 patients, 18–50 years old, treated with 1–2 antipsychotic medications (≥12 weeks on current drug and ≥35 days on current dose before treatment) who have functional impairment in day-to-day activities and interact ≥1 hour per week with a designated study partner. Patients with cognitive impairment due to developmental, neurological or other disorders, with a current DSM-5 diagnosis other than schizophrenia or receiving cognitive remediation therapy within 12 weeks prior to screening, will be excluded. Patients will be recruited from multiple centres across 41 countries in Asia, North and South America, Europe and the Asia-Pacific Region, and randomised 1:1 to receive either iclepertin 10 mg (oral administration; n=293), or placebo (n=293) once daily for 26 weeks. The primary endpoint is change from baseline in overall composite T-score of the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery. The key secondary endpoints are change from baseline in total score on the Schizophrenia Cognition Rating Scale and change from baseline in the adjusted total time T-score in the Virtual Reality Functional Capacity Assessment Tool. Results: The CONNEX programme is currently recruiting (Table); the first patients were enrolled in Aug–Sept 2021 and completion is expected in Q1 2025. The presentation will describe the current study status, information relating to screening failures, and the experience of collecting these data as part of a large multi-country, multicentre study. Table. The number of patients recruited by 31 August 2023 CONNEX 1 CONNEX 2 CONNEX 3 Screened 565 521 493 Randomised 409 360 350 Completed trial medication 202 184 191 Conclusions: Iclepertin may represent the first efficacious medication for cognitive impairment associated with schizophrenia. Funding: Boehringer Ingelheim Disclosure of Interest: C. Reuteman-Fowler Employee of: Boehringer Ingelheim, Z. Blahova Employee of: Boehringer Ingelheim, S. Ikezawa Consultant of: Boehringer Ingelheim Pharma GmbH, Lundbeck, Takeda Pharma, Sumitomo Dainippon Pharma, Employee of: International University of Health and Welfare, Mita Hospital, Tokyo, Japan, S. Marder Consultant of: Boehringer Ingelheim Pharma GmbH, Merck, Biogen and Sunovion, P. Falkai Consultant of: Boehringer Ingelheim Pharma GmbH, Boehringer Ingelheim Pharma Advisory Board, J. H. Krystal Shareolder of: Freedom Biosciences, Inc., Biohaven Pharmaceuticals, Sage Pharmaceuticals, Spring Care, Biohaven Pharmaceuticals Medical Sciences, EpiVario, RBNC Therapeutics, Terran Biosciences and Tempero Bio, Consultant of: Aptinyx, Atai Life Sciences, AstraZeneca Pharmaceuticals, Biogen, Biomedisyn Corporation, Bionomics, Boehringer Ingelheim International, Cadent Therapeutics, Clexio Bioscience, COMPASS Pathways, Concert Pharmaceuticals, Epiodyne, EpiVario, Greenwich Biosciences, Heptares Therapeutics, Janssen, Jazz Pharmaceuticals, Otsuka America Pharmaceutical, Perception Neuroscience Holdings, Spring Care, Sunovion Pharmaceuticals, Takeda Industries, Taisho Pharmaceutical Co.; Biohaven Pharmaceuticals, BioXcel Therapeutics, Cadent Therapeutics, Cerevel Therapeutics, Delix Therapeutics, EpiVario, Eisai, Jazz Pharmaceuticals, Novartis, PsychoGenics, RBNC Therapeutics, Tempero Bio and Terran Biosciences Advisory Boards [ABSTRACT FROM AUTHOR]

A co-axial copper tube measurement device is developed to measure AC losses of the High Temperature Superconducting (HTS) tapes. The experimental data indicate that the inductive voltages are proportional to the frequency and therefore the main loss depends on hysteresis loss.