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Background: Considering diversity, equity, and inclusion (DEI) in clinical trials ensures that data collected for investigational treatments reflect the populations most likely to benefit from those therapies. Resources and recommendations regarding DEI were assembled by the trial sponsor to assist clinical trial development., Methods: A cross-disciplinary team from the sponsoring organization was assembled to inform trial planning and collate resources that promote DEI throughout the clinical trial life cycle., Results: Representatives from clinical operations, health economic outcomes research, medical affairs, patient advocacy, procurement, and research and development functional groups united together to implement DEI strategies in clinical trials. Planning strategies focus on eligibility, participant/patient engagement, feedback through patient advocacy organizations, and community interactions. Informed site, investigator, and vendor selection at trial startup supports efforts to recruit diverse target trial populations and engage underrepresented businesses; establishing relationships and demographic target-goal tracking should be maintained throughout trial management. Continued communication during trial closeout consolidates learnings and enhances partnerships with trial participants and patient advocacy organizations. The sponsoring organization continuously updates an internal library of resources to facilitate implementation of outlined strategies., Conclusions: This first iteration of guidance intends to improve the representation of target populations who will ultimately benefit from investigational therapies; to assist sponsor clinical trial teams in developing recruitment and retention plans; and to ensure compliance with federal granting agencies. The sponsoring organization anticipates data from future clinical trials will help characterize the impact of these initiatives to ensure evidence-based practices are used in future clinical trials to enhance DEI., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors are employees of Cerevel Therapeutics and may hold stock or stock options in the company., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Emraclidine is a novel, brain-penetrant, highly selective M4 receptor positive allosteric modulator in development for the treatment of schizophrenia. We aimed to evaluate the safety and tolerability of multiple ascending doses of emraclidine in patients with schizophrenia., Methods: We conducted a two-part, randomised, phase 1b trial in the USA. Eligible participants were aged 18-50 years (part A) or 18-55 years (part B) with a primary diagnosis of schizophrenia per the Diagnostic and Statistical Manual of Mental Disorders 5th edition, as confirmed by the Mini International Neuropsychiatric Interview, and extrapyramidal symptom assessments indicating normal to mild symptoms at screening. Part A evaluated the safety and tolerability of emraclidine in five cohorts of participants with stable schizophrenia who received ascending oral doses of emraclidine 5-40 mg (40 mg was administered as 20 mg twice daily) or placebo at a single US site. Part B was a double-blind, randomised, placebo-controlled study that enrolled adults with acute schizophrenia across five US sites; participants were randomly assigned (1:1:1) to receive emraclidine 30 mg once daily, emraclidine 20 mg twice daily, or placebo for 6 weeks (doses established in part A). The primary endpoint was safety and tolerability, assessed in the safety population (participants who received at least one dose of emraclidine or placebo). This trial is now complete and is registered with ClinicalTrials.gov, NCT04136873., Findings: Between Sept 23, 2019, and Sept 17, 2020, 118 patients were assessed for eligibility and 49 were randomly assigned across five cohorts in part A. 44 participants completed the study, with 36 participants receiving emraclidine and eight receiving placebo. The two highest doses tested were selected for part B. Between Oct 12, 2020, and May 7, 2021, 148 patients were assessed for eligibility and 81 were randomly assigned to emraclidine 30 mg once daily (n=27), emraclidine 20 mg twice daily (n=27), or placebo (n=27) in part B. Incidence of adverse events (14 [52%] of 27 participants in the emraclidine 30 mg once daily group, 15 [56%] of 27 in the emraclidine 20 mg twice daily group, and 14 [52%] of 27 in the placebo group), clinical assessments, and weight changes were similar across groups. The most common adverse event was headache (15 [28%] of 54 participants in the emraclidine groups, seven [26%] of 27 in the placebo group). Modest, transient increases in blood pressure and heart rate in emraclidine groups observed at treatment initiation diminished over time and were not considered clinically meaningful by week 6., Interpretation: These data support further investigation of emraclidine as a once-daily treatment for schizophrenia without need for titration and with a potentially favourable side-effect profile., Funding: Cerevel Therapeutics., Competing Interests: Declaration of interests JHK reports consulting agreements with Aptinyx, Atai Life Sciences, AstraZeneca, Biogen Idec, Biomedisyn Corporation, Bionomics, Boehringer Ingelheim International, Cadent Therapeutics, Clexio Bioscience, COMPASS Pathways, Concert Pharmaceuticals, Eisai, Epiodyne, EpiVario, Greenwich Biosciences, Heptares Therapeutics, Janssen Research & Development, Jazz Pharmaceuticals, Lohocla Research Corporation, Novartis, Otsuka America Pharmaceutical, Perception Neuroscience Holdings, PsychoGenics, RBNC Therapeutics, Spring Care, Sunovion Pharmaceuticals, Taisho Pharmaceutical Holdings, Takeda Industries, Tempero Bio, and Terran Biosciences; serves on the scientific advisory boards of Biohaven Pharmaceuticals, BioXcel Therapeutics (Clinical Advisory Board), Cadent Therapeutics (Clinical Advisory Board), and Cerevel Therapeutics; holds consulting agreements with EpiVario, Eisai, Jazz Pharmaceuticals, Lohocla Research Corporation, Novartis, PsychoGenics, RBNC Therapeutics, Tempero Bio, and Terran Biosciences; serves on the Board of Directors for Freedom Biosciences and holds stock or stock options in Biohaven Pharmaceuticals, Sage Pharmaceuticals, Spring Care, Biohaven Pharmaceuticals Medical Sciences, EpiVario, RBNC Therapeutics, Terran Biosciences, and Tempero Bio; has received research support from AstraZeneca, Novartis, and Cerevel Therapeutics; and serves as Editor of Biological Psychiatry and is a named inventor on a number of patents and patent applications—most recently, US Provisional Patent Application 63/125,181, filed on Dec 14, 2020. JMK has been a consultant or adviser to or has received honoraria from Acadia, Alkermes, Allergan, Cerevel Therapeutics, IntraCellular Therapies, Janssen or Johnson & Johnson, Karuna, LB Pharma, Lundbeck, Lyndra, Medscape, Merck, Neurocrine, Otsuka, Reviva, Roche, Sumitomo Dainippon, Saladex, Sunovion, Takeda, and Teva; has received grant support from Janssen, Lundbeck, Otsuka, and Sunovion; and is a shareholder of LB Pharma and a shareholder in Vanguard Research Group. CUC has been a consultant or adviser to or has received honoraria from AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Axsome Therapeutics, Cerevel Therapeutics, Compass, Damitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen or Johnson & Johnson, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Medscape, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Segirus, Servier, SK Life Science, Sumitomo Dainippon, Sunovion, Supernus, Takeda, Teva, and Viatris; has provided expert testimony for Janssen and Otsuka; has served on a Data Safety Monitoring Board for Lundbeck, Rovi, Supernus, and Teva; has received grant support from Janssen and Takeda; and has received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Mindpax, and LB Pharma. DPW reports grants and research support from AbbVie, Acadia, Alkermes, Allergan, Avanir, Biogen, Boehringer Ingelheim, Cerevel, Indivior, IntraCellular, Janssen, Johnson & Johnson Research and Development, Lundbeck, Lupin, Lyndra, Novartis, Noven, Otsuka, Pfizer, Roche, Sunovion, and Takeda; has been a consultant for Biogen, Boehringer Ingelheim, Janssen, Lyndra, and Otsuka; and served as principal investigator on this trial. ML, SD, SP, IC, PI, LF, SV, PP, RS, and JR are employees of Cerevel Therapeutics and might hold stock or stock options in the company., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Available essential tremor (ET) therapies have limitations., Objectives: The objective of this study was to evaluate CX-8998, a selective T-type calcium channel modulator, in essential tremor., Methods: Patients 18-75 years old with moderate to severe essential tremor were randomized 1:1 to receive CX-8998 (titrated to 10 mg twice daily) or placebo. The primary end point was change from baseline to day 28 in The Essential Tremor Rating Assessment Scale performance subscale scored by independent blinded video raters. Secondary outcomes included in-person blinded investigator rating of The Essential Tremor Rating Assessment Scale performance subscale, The Essential Tremor Rating Assessment Scale activities of daily living subscale, and Kinesia ONE accelerometry., Results: The video-rated The Essential Tremor Rating Assessment Scale performance subscale was not different for CX-8998 (n = 39) versus placebo (n = 44; P = 0.696). CX-8998 improved investigator-rated The Essential Tremor Rating Assessment Scale performance subscale (P = 0.017) and The Essential Tremor Rating Assessment Scale activities of daily living (P = 0.049) but not Kinesia ONE (P = 0.421). Adverse events with CX-8998 included dizziness (21%), headache (8%), euphoric mood (6%), and insomnia (6%)., Conclusions: The primary efficacy end point was not met; however, CX-8998 improved some assessments of essential tremor, supporting further clinical investigation. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA., (© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)