138 Efficacy and Safety of SEP-363856, a Novel Psychotropic Agent with a Non-D2 Mechanism of Action, in the Treatment of Schizophrenia

Abstract:Background:SEP-363856 is a novel psychotropic agent that has shown broad efficacy in animal models of schizophrenia and depression. Its antipsychotic effects appear to be mediated by agonist activity at both trace amine-associated receptor 1 (TAAR1) and 5-HT1A receptors. Notably, SEP-363856 does not bind to any dopaminergic, serotonergic (except 5-HT1A), glutamatergic, or other neuroreceptors thought to mediate the effects of currently available antipsychotics. The aim of this study was to evaluate the efficacy and safety of SEP-363856 in acutely symptomatic patients with schizophrenia.Method:Patients aged 18-40 years meeting DSM-5 criteria for schizophrenia (PANSS total score ≥80) were randomized, double-blind, to 4-weeks of flexible-dose SEP-363856 (50 or 75 mg/d) or placebo. Efficacy measures included the Positive and Negative Syndrome Scale (PANSS) total score (primary), PANSS subscale scores, and the Clinical Global Impressions-Severity (CGI-S) score. Change from baseline in primary and secondary measures were analyzed using a mixed model for repeated measures (MMRM) analysis.Results:Study treatment groups were similar at baseline: SEP-363856 (N=120; male, 64.2%; mean age, 30.0 years; PANSS total score, 101.4) and placebo (N=125; male, 63.2%; mean age, 30.6 years; PANSS total score, 99.7). Least-squares (LS) mean reduction from baseline to week 4 was significantly greater for SEP-363856 vs. placebo on the PANSS total score (-17.2 vs. -9.7; P=0.001; effect size, 0.45), PANSS positive subscale score (-5.5 vs. -3.9; P=0.019; effect size, 0.32), PANSS negative subscale score (-3.1 vs. -1.6; P=0.008; effect size, 0.37), PANSS general psychopathology subscale score (-9.0 vs. -4.7; P<0.001; effect size, 0.51), and the CGI-Severity score (-1.0 vs. -0.5; P<0.001; effect size, 0.52). Discontinuation rates for SEP-363856 vs. placebo were similar overall (21.7% vs. 20.8%) and due to an adverse event (8.3% vs. 6.4%). Change in weight, lipids, glucose and prolactin was similar in SEP-363856 and placebo groups. Adverse events occurring with an incidence ≥2% on SEP-363856 or placebo (with SEP-363856 incidence higher than placebo) were: somnolence (6.7% vs. 4.8%), agitation (5.0% vs. 4.8%), nausea (5.0% vs. 3.2%), diarrhea (2.5% vs. 0.8%), and dyspepsia (2.5% vs. 0%). The proportion of patients who reported any extrapyramidal symptom was 3.3% on SEP-363856 and 3.2% on placebo.Conclusion:In this placebo-controlled study, treatment with SEP-363856, a novel psychotropic agent, was associated with statistically significant and clinically meaningful improvement in schizophrenia symptoms as demonstrated by endpoint change in PANSS total and subscale scores, and CGI-Severity scores. Safety and tolerability findings for SEP-363856 were in general similar to placebo. In particular, SEP-363856 was not associated with extrapyramidal symptoms, akathisia, or hyperprolactinemia, consistent with its non-D2 mechanism of action.ClinicalTrials.gov:NCT02969382Funding Acknowledgements:Supported by funding from Sunovion Pharmaceuticals Inc.

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The Efficacy of Lurasidone on PANSS Subscales in Adolescent Patients with Schizophrenia: Results from a 6-week, Double-blind, Placebo-controlled, Multicenter Study

European Psychiatry ◽

10.1016/j.eurpsy.2017.01.284 ◽

2017 ◽

Vol 41 (S1) ◽

pp. S90-S91 ◽

Cited By ~ 1

Author(s):

C. Correll ◽

R. Goldman ◽

J. Cucchiaro ◽

L. Deng ◽

A. Loebel

Keyword(s):

Repeated Measures ◽

Mixed Model ◽

Wide Spectrum ◽

Dose Range ◽

Data Safety Monitoring Board ◽

Double Blind ◽

Meaningful Improvement ◽

General Psychopathology ◽

Adolescent Patients ◽

Adjusted Least Squares

IntroductionLurasidone is an atypical antipsychotic that demonstrated efficacy in the treatment of adults with schizophrenia in the dose range of 37–148 mg/day.Objective/AimsThe objective of this analysis was to evaluate the efficacy of lurasidone in adolescent patients with schizophrenia.MethodsAdolescents (13–17 years old) diagnosed with schizophrenia were randomly assigned to six weeks of double-blind treatment with lurasidone 37 mg/day, 74 mg/day or placebo. Changes from baseline to week 6 in PANSS total and subscale (positive, negative, general psychopathology, excitability) scores were evaluated using mixed-model repeated-measures analysis.ResultsA total of 326 patients (mean age, 15.4 years) were randomized and received lurasidone 37 mg/day (n = 108), 74 mg/day (n = 106), or placebo (n = 112). The PANSS total score at week 6 demonstrated a placebo-adjusted, least-squares (LS) mean improvement of –8.0 (P < 0.001; effect size [ES], 0.51) for the 37 mg/day group and –7.7 (P < 0.001; ES = 0.48) for the 74 mg/day group. Placebo-adjusted LS mean change for lurasidone 37 mg/day and 74 mg/day, respectively, was –3.2 (P < 0.001; ES = 0.62) and –3.2 (P < 0.001; ES = 0.60) on the PANSS positive subscale, –1.7 (P = 0.011; ES = 0.41) and –1.6 (P = 0.022; ES = 0.35) on the PANSS negative subscale, –2.8 (P = 0.012; ES = 0.38) and –2.8 (P = 0.011; ES = 0.37) on the PANSS general psychopathology subscale, and –1.1 (P = 0.016; ES = 0.36) and –1.8 (P < 0.001; ES = 0.53) on the PANSS excitability subscale.ConclusionsIn adolescent patients with schizophrenia, lurasidone (37 mg/day and 74 mg/day) demonstrated statistically significant efficacy and clinically meaningful improvement across a wide spectrum of symptoms associated with schizophrenia. Sponsored by Sunovion Pharmaceuticals Inc. ClinicalTrials.gov identifier: NCT01911429.Disclosure of interestDr Correll reports being a consultant and/or advisor for Alkermes, Forum Pharmaceuticals Inc., Gerson Lehrman Group, IntraCellular Therapies, Janssen/J&J, Lundbeck, Medavante, Medscape, Otsuka, Pfizer Inc, ProPhase, Sunovion Pharmaceuticals Inc., Supernus, Takeda, and Teva providing expert testimony for Bristol-Myers Squibb Company, Janssen, and Otsuka serving on a Data Safety Monitoring Board for Lundbeck and Pfizer Inc and receiving grant support from Takeda. Drs Goldman, Cucchiaro, Deng and Loebel are employees of Sunovion Pharmaceuticals Inc.

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P210 Efficacy and safety of filgotinib for patients with RA with inadequate response to methotrexate: FINCH1 primary outcome results

Rheumatology ◽

10.1093/rheumatology/keaa111.205 ◽

2020 ◽

Vol 59 (Supplement_2) ◽

Author(s):

David Walker ◽

Bernard G Combe ◽

Alan J Kivitiz ◽

Yoshiya Tanaka ◽

Désirée van der Heijde ◽

...

Keyword(s):

Repeated Measures ◽

Study Drug ◽

Janus Kinase ◽

Controlled Study ◽

Stock Ownership ◽

Inadequate Response ◽

Efficacy And Safety ◽

Double Blind ◽

Mixed Effect ◽

Patient Reported

Abstract Background Filgotinib (FIL) is an oral, potent, selective Janus kinase 1 inhibitor that has shown good efficacy and was well tolerated for treatment of rheumatoid arthritis (RA). The objective of this study was to evaluate efficacy and safety of FIL treatment in patients with RA who have had an inadequate response to methotrexate (MTX). Methods This Phase 3, double-blind, active- and placebo (PBO)-controlled study randomised patients with active RA (3:3:2:3) to FIL 200mg, FIL 100mg, adalimumab [ADA] 40mg every 2 weeks, or PBO daily for up to 52 weeks; results through week 24 are presented. Patients also received background MTX. Primary efficacy endpoint was proportion of patients achieving ACR20 at week 12; additional clinical assessments included ACR50 and ACR70 and DAS28-CRP score ≤3.2 and <2.6, and patient-reported outcomes including HAQ-DI. Safety endpoints included adverse event types and rates. Logistic regression was used for superiority test of FIL vs PBO for ACR response and other binary endpoints, while mixed-effect model for repeated measures (MMRM) were used for continuous endpoints. Non-inferiority test of FIL to ADA (preserving >50% of ADA response) was performed for DAS28-CRP ≤3.2 and <2.6. Results Of 1,759 patients randomised, 1,755 received study drug: 475 FIL 200mg; 480 FIL 100mg; 325 ADA; and 475 PBO, of which 89.5%, 90.4%, 88.9%, and 81.3%, respectively, completed 24 weeks of study drug. 81.8% were female, mean (standard deviation [SD]) duration of RA was 7.8 (7.6) years, and mean (SD) DAS28-CRP was 5.7 (0.9). At week 12, significantly more patients in the FIL 200mg and 100mg arms achieved an ACR20 improvement vs PBO (Table 1). More patients receiving FIL achieved ACR50 and ACR70 improvements, DAS28-CRP scores ≤3.2 and <2.6 and reported improvements in HAQ-DI scores versus PBO (Table 1). Non-inferiority of FIL 200mg to ADA was met based on DAS28-CRP ≤3.2. The FIL safety profile was consistent with prior studies through Week 24. Conclusion FIL 200mg and 100mg led to significant improvement in signs and symptoms of RA, prevented radiographic progression, improved physical function compared to PBO, and was well-tolerated. Efficacy of FIL 200mg was non-inferior to ADA based on DAS28-CRP ≤3.2. Disclosures D. Walker: Other; Received support from Lilly, Pfizer, Novartis and Roche. B.G. Combe: Honoraria; Received honoraria from AbbVie, BMS, Gilead, Janssen, Eli Lilly and Co., MSD, Novartis, Pfizer, Roche-Chugai, Sanofi and UCB. A.J. Kivitiz: Consultancies; Consultant to AbbVie, Celgene, Horizon, Jansses, Merck, Novartis, Pfizer, UCB, Genzyme, Sanofi, Regeneron, SUN Pharma Advanced Research, Boehringer Ingelheim, Flexion and Novartis. Shareholder/stock ownership; Shareholder of Novartis. Y. Tanaka: Honoraria; Honoraria from Daiichi-Sankyo, Astellas, Chugai, Eli Lilly ans Co., Pfizer, AbbVie, YL Biologics, BMS, Takeda, Misubishi-Tanabe, Novartis, Eisai, Janssen, Teijin. Grants/research support; Grant support from Asahi-Kasei, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, BMS, UCB, Daiichi-Sankyo, Eisai, Ono, Astellas, Eli Lilly, Pfizer, Abbvi and YL. D. van der Heijde: Corporate appointments; Director of Imaging Rheumatology bv. Consultancies; Consultant for consultant for AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Daiichi, Eli Lilly, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, and UCB. F. Matzkies: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. B. Bartok: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. L. Ye: Corporate appointments; Employee of Gilead Sciences, Inc.. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. Y. Guo: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. C. Tasset: Corporate appointments; Employee of Galapagos NV. J.S. Sundy: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. N. Mozaffarian: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. R.B.M. Landewé: Consultancies; Consultant for AbbVie, AstraZeneca, BMS, Galapagos, Pfizer, Eli Lilly, Novartis, and UCB.. S. Bae: None. E.C. Keystone: Consultancies; Consultant for AbbVie, Amgen, AstraZeneca Pharma, Biotest, BMS Canada, Celltrion, Crescendo, Bioscience, F.Hoffman-La Roche Inc., Genentech, Janssen, Eli Lilly and Co., Merck, Pfizer,, PuraPharm, Sandoz, Sanofi-Aventis, Sanofi-Genzyme, Samsumg Bioepsis, and UCB. P. Nash: Consultancies; Consultant for AbbVie, BMS, Jansses, Pfizer, Roche, Lilly, Sanofi, MSD, Novartis, Celgene and Gilead.

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Efficacy of lurasidone across five symptom dimensions of schizophrenia: Pooled analysis of short-term, placebo-controlled studies

European Psychiatry ◽

10.1016/j.eurpsy.2014.08.001 ◽

2015 ◽

Vol 30 (1) ◽

pp. 26-31 ◽

Cited By ~ 16

Author(s):

A. Loebel ◽

J. Cucchiaro ◽

R. Silva ◽

Y. Mao ◽

J. Xu ◽

...

Keyword(s):

Effect Size ◽

Repeated Measures ◽

Negative Symptoms ◽

Mixed Model ◽

Five Factor Model ◽

Pooled Analysis ◽

Positive Symptoms ◽

Factor Scores ◽

Short Term ◽

Double Blind

AbstractObjective:To evaluate the efficacy of lurasidone for schizophrenia using an established five-factor model of the Positive and Negative Syndrome Scale (PANSS).Methods:Patient-level data were pooled from five randomized, double-blind, placebo-controlled, 6-week studies of lurasidone (fixed doses, 40–160 mg/d) for patients with an acute exacerbation of schizophrenia. Changes in five established PANSS factors were assessed using mixed-model repeated measures analysis.Results:Compared with placebo (n = 496), lurasidone (n = 1029, dose groups pooled) significantly improved the PANSS total score at Week 6 (−22.6 vs. −12.8; P < 0.001; effect size, 0.45), as well as all factor scores (P < 0.001 for each): positive symptoms (−8.4 vs. −6.0; effect size, 0.43), negative symptoms (−5.2 vs. −3.3; effect size, 0.33), disorganized thought (−4.9 vs. −2.8; effect size, 0.42), hostility/excitement (−2.7 vs. −1.6; effect size, 0.31), and depression/anxiety (−3.2 vs. −2.3; effect size, 0.31). Separation from placebo occurred at Week 1 for the positive symptoms, disorganized thought, and hostility/excitement factors and at Week 2 for the other factors.Conclusions:In this pooled analysis of short-term studies in patients with acute schizophrenia, lurasidone demonstrated significant improvement for each of the five PANSS factor scores, indicating effectiveness across the spectrum of schizophrenia symptoms.

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108 Lurasidone in Children and Adolescents With Bipolar Depression Presenting With Mixed Features

CNS Spectrums ◽

10.1017/s1092852918000081 ◽

2018 ◽

Vol 23 (1) ◽

pp. 70-70

Author(s):

Cynthia Siu ◽

Andrei Pikalov ◽

Michael Tocco ◽

Antony Loebel

Keyword(s):

Children And Adolescents ◽

Effect Size ◽

Repeated Measures ◽

Mixed Model ◽

Rating Scale ◽

Bipolar Depression ◽

Depression Score ◽

Double Blind ◽

Increased Risk ◽

Mixed Features

AbstractObjectiveTo evaluate the efficacy and safety of lurasidone in the treatment of children and adolescents with bipolar depression presenting with mixed features.MethodsPatients 10 to 17 years of age, inclusive, with a DSM-IV-TR diagnosis of bipolar I depression, were randomized to 6 weeks of double-blind treatment with once-daily, flexible doses of lurasidone 20-80 mg or placebo. The presence of mixed features (subthreshold hypomanic symptoms) was defined as a YMRS score > 5 at study baseline. Efficacy analyses included change from baseline to week 6 in Children Depression Rating Scale, Revised (CDRS-R) score (the primary outcome), and Clinical Global Impressions, Bipolar Severity of Depression Score (CGI-BP-S), using mixed model for repeated measures (MMRM) analysis.ResultsAt baseline, mixed features were present in 54.2% of patients (lurasidone, n=97/173; placebo, n=89/170). Treatment with lurasidone (vs placebo) was associated with significantly greater reductions in CDRS-R scores at week 6 in the mixed features group (-21.5 vs -15.9; P<0.01; effect size, 0.45), and in the group without mixed features (-20.4 vs -14.8; P<0.01; effect size, 0.45). Likewise, lurasidone was associated with greater effect size (vs placebo) for reductions inCGI-BP-S scores at week 6 in the mixed features group (-1.6 vs -1.1; P<0.001; effect size 0.57), and in the group without mixed features (-1.3 vs -1.0; P=0.05; effect size 0.30). Rates of protocol-defined treatment-emergent hypomania or mania were similar for lurasidone and placebo in patients with mixed features(lurasidone 8.2% vs. placebo 9.0%) and without mixed features (lurasidone 1.3% vs. placebo 3.7%).ConclusionsIn this post-hoc analysis, lurasidone was found to be efficacious for treating child and adolescent patients with bipolar depression presenting with mixed features(assessed cross-sectionally at study baseline). There was no increased risk of treatment-emergent mania observed in patients with or without mixed features.Funding AcknowledgementsSunovion Pharmaceuticals Inc.

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179 Dasotraline in Children With Attention Deficit Hyperactivity Disorder: Results of a Randomized, Double-Blind, Placebo-Controlled Study

CNS Spectrums ◽

10.1017/s1092852918000615 ◽

2018 ◽

Vol 23 (1) ◽

pp. 102-103

Author(s):

Robert Goldman ◽

Lenard Adler ◽

Thomas Spencer ◽

Robert Findling ◽

Seth C. Hopkins ◽

...

Keyword(s):

Weight Loss ◽

Repeated Measures ◽

Mixed Model ◽

Rating Scale ◽

Plasma Concentrations ◽

Fixed Dose ◽

Controlled Study ◽

Double Blind ◽

Once Daily ◽

Stable Plasma

AbstractObjectivesOnce-daily dosing with dasotraline, a novel dopamine and norepinephrine reuptake inhibitor, achieves stable plasma concentrations over 24 hours with once-daily dosing. This study evaluated dasotraline in children aged 6–12 years (NCT02428088).MethodsPatients were randomized 1:1:1 to 6 weeks of once-daily, fixed-dose dasotraline 2 or 4 mg/day, or placebo. The primary efficacy endpoint was change from baseline (CFB) at Week 6 in ADHD Rating Scale Version IV – Home Version (ADHD RS-IV HV) total score, using a mixed model for repeated measures (MMRM) in the intent-to-treat (ITT) population. Secondary endpoints included Clinical Global Impression-Severity (CGI-S) score and safety endpoints.ResultsThe mean age of 342 randomized patients was 9.1 [SD: 1.9] years; 66.7% were male. Overall, 79% of patients completed the study. In the ITT population (N=336), ADHD RS-IV HV total score improved significantly with dasotraline 4 mg/day vs placebo(least squares [LS] mean [SE] CFB at Week 6: –17.53 [±1.31] vs –11.36 [±1.29], respectively, p<0.001; effect size [ES]: 0.48). Inattentiveness and hyperactivity/impulsivity subscale scores significantly improved with 4 mg/day vs placebo at Week 6 (p=0.001, p=0.003, respectively). Improvement in CGI-S score was statistically significant with dasotraline 4 mg/day vs placebo(LS mean [SE] CFB at Week 6: –1.39 [±0.12] vs –1.04 [±0.12], respectively, p=0.040; ES: 0.29). No significant improvement was observed on the ADHD RS-IV HV total score and the CGI-S score for dasotraline 2 mg/day vs placebo. The most frequent treatment-emergent AEs (≥5% and higher than placebo) were (2 mg/day; 4 mg/day; placebo): insomnia (15.3%; 21.7%; 4.3%, all terms combined), decreased appetite (12.6%; 21.7%; 5.2%), weight loss (5.4%; 8.7%; 0%), irritability (3.6%; 7.0%; 6.0%), nasopharyngitis (0.9%; 5.2%; 0.9%), and nausea (0%; 5.2%; 2.6%).ConclusionsCompared with placebo, dasotraline 4 mg/day significantly improved ADHD symptoms in children, as assessed by ADHD RS-IV HV total score and inattentiveness and hyperactivity/impulsivity subscale scores. Dasotraline was generally well tolerated; most common AEs were insomnia, decreased appetite, weight loss and irritability.Funding AcknowledgementsStudy sponsored by Sunovion Pharmaceuticals Inc.

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A phase 3 randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of GS-5745 combined with mFOLFOX6 as first-line treatment in patients with advanced gastric or gastroesophageal junction adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.tps4139 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. TPS4139-TPS4139 ◽

Cited By ~ 3

Author(s):

Johanna C. Bendell ◽

Alexander Starodub ◽

Xi Huang ◽

Julia D. Maltzman ◽

Zev A. Wainberg ◽

...

Keyword(s):

Disease Progression ◽

Treatment Cycle ◽

Day Treatment ◽

Gastroesophageal Junction ◽

Controlled Study ◽

Efficacy And Safety ◽

Phase 3 ◽

Double Blind ◽

Meaningful Improvement ◽

Primary Tumor Site

TPS4139 Background: GS-5745 is a monoclonal antibody that inhibits matrix metalloproteinase 9 (MMP9), an extracellular enzyme involved in matrix remodeling, tumor growth, and metastasis. Inhibiting MMP9 blocks paracrine signaling and metastasis and alters the tumor immune microenvironment. GS-5745 (800 mg q 2 weeks) with mFOLFOX6 was examined in a Phase 1b study in 40 patients with gastric and GEJ adenocarcinoma (GS-US-296-0101), and demonstrated encouraging activity without added toxicity (10% CR, median PFS 10.7 mo (Shah et al ASCO GI 2017, a108)). Decreased free MMP9 suggested inhibition of MMP9 enzymatic activity by GS-5745. These data support the hypothesis that GS-5745 treatment inhibits MMP9 activity and that the inhibition may lead to improved clinical outcomes. Methods: This phase 3, randomized, double-blind, multicenter study investigates the efficacy and safety of GS-5745 combined with mFOLFOX6 in subjects with untreated gastric and GEJ adenocarcinoma. Total of 430 eligible subjects with advanced gastric and GEJ cancer will be randomized in a 1:1 manner to mFOLFOX6 plus GS-5745 or mFOLFOX6 plus placebo. Stratification factors include ECOG status (0 v 1), geographic region (Latin America v All other countries), and primary tumor site (gastric v GEJ). CT or MRI scans will be performed every 8 weeks to evaluate response to treatment. mFOLFOX6 will be administered on Days 1 and 15 of each 28-day treatment cycle for a total of 6 cycles followed thereafter by leucovorin (LV) and 5-fluorouracil (5-FU) dosing on Days 1 and 15 of each 28-day treatment cycle until disease progression. GS-5745/placebo 800 mg will be infused on Days 1 and Day 15 of each 28 day cycle until disease progression. Primary endpoint is OS, and secondary endpoints include PFS, ORR (RECIST 1.1), and safety. The study is designed to have an 85% power to detect clinically meaningful improvement in overall survival at the one-sided significance level of 0.025. The association of exploratory biomarkers with study drug response will also be evaluated. Enrollment opened Oct. 2015. Clinical trial information: NCT02545504.

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A phase 3 randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of GS-5745 combined with mFOLFOX6 as first-line treatment in patients with advanced gastric or gastroesophageal junction adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.tps217 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. TPS217-TPS217

Author(s):

Johanna C. Bendell ◽

Alexander Starodub ◽

Xi Huang ◽

Julia D. Maltzman ◽

Zev A. Wainberg ◽

...

Keyword(s):

Disease Progression ◽

Treatment Cycle ◽

Day Treatment ◽

Gastroesophageal Junction ◽

Controlled Study ◽

Efficacy And Safety ◽

Phase 3 ◽

Double Blind ◽

Meaningful Improvement ◽

Primary Tumor Site

TPS217 Background: GS-5745 is a monoclonal antibody that inhibits matrix metalloproteinase 9 (MMP9), an extracellular enzyme involved in matrix remodeling, tumor growth, and metastasis. Inhibiting MMP9 is expected to block paracrine signaling and metastasis and to alter the immune microenvironment within the tumor. GS-5745 (800 mg every 2 weeks) with mFOLFOX6 was examined in a Phase 1b study in 40 patients with gastric and GEJ adenocarcinoma (GS-US-296-0101), and demonstrated encouraging activity without added toxicity. Additionally, decreased serum biomarkers suggested inhibition of MMP9 enzymatic activity by these agents. These data support the hypothesis that GS-5745 treatment inhibits MMP9 activity and that the inhibition may lead to improved clinical outcomes. Methods: This phase 3, randomized, double-blind, multicenter study investigates the efficacy and safety of GS-5745 combined with mFOLFOX6 in subjects with untreated gastric and GEJ adenocarcinoma. Total of 430 eligible subjects with advanced gastric and GEJ cancer will be randomized in a 1:1 manner to mFOLFOX6 plus GS-5745 or mFOLFOX6 plus placebo. Stratification factors include ECOG status (0 v 1), geographic region (Latin America v All other countries), and primary tumor site (gastric v GEJ). CT or MRI scans will be performed every 8 weeks to evaluate response to treatment. mFOLFOX6 will be administered on Days 1 and 15 of each 28-day treatment cycle for a total of 6 cycles followed thereafter by leucovorin (LV) and 5-fluorouracil (5-FU) dosing on Days 1 and 15 of each 28-day treatment cycle until disease progression. GS-5745/placebo 800 mg will be infused on Days 1 and Day 15 of each 28 day cycle until disease progression. Primary endpoint is OS, and secondary endpoints include PFS, ORR (RECIST 1.1), and safety. The study is designed to have an 85% power to detect clinically meaningful improvement in overall survival at the one-sided significance level of 0.025. The association of exploratory biomarkers with study drug response will also be evaluated. Enrollment opened Oct. 2015. Clinical trial information: NCT02545504.

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0635 Effects of Donepezil in Patients with Residual Excessive Sleepiness of Obstructive Sleep Apnea: A Double Blind; Randomized Placebo; Controlled Study

SLEEP ◽

10.1093/sleep/zsaa056.631 ◽

2020 ◽

Vol 43 (Supplement_1) ◽

pp. A242-A242

Author(s):

K M Sousa ◽

R D Piovezan ◽

L e Silva ◽

C De melo ◽

D Poyares ◽

...

Keyword(s):

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Effect Size ◽

Repeated Measures ◽

Performance Test ◽

Controlled Study ◽

National Council ◽

Double Blind ◽

Excessive Sleepiness ◽

Obstructive Sleep

Abstract Introduction Residual excessive sleepiness (RES) is presented by 6% of obstructive sleep apnea patients despite effective CPAP therapy. Few interventions have been tested for this condition and are focused on daytime stimulants. Recently, cholinergic activity decline was suggested as a potential mechanism in the pathophysiology of RES. This study aimed to investigate the effects of donepezil, an anticholinesterase inhibitor, in patients with RES. Methods This double-blind, randomized, placebo-controlled crossover study included participants with RES (35-65 years). Neuropsychiatric disorders, alcoholism, smoking, shiftwork, psychoactive drugs, other sleep disorders were exclusion criteria. Participants were assigned to one intervention arm (donepezil 5 mg for 15 days followed by donepezil 10mg for 15 days or placebo in the morning). After a 20-day wash-out, the same procedure was repeated following the crossover design. Somnolence measured by the Epworth sleepiness scale (ESS) and Maintenance of Wakefulness Test (MWT) were the primary endpoints. PSG, cognitive (trail test, continuous performance test) and Beck’s depression scale parameters were secondary endpoints. General Linear Models for repeated measures compared interventions responses. Cohen’s d measured effect sizes. Adverse events (AEs) were assessed by questionnaire. Results The study enrolled eight individuals. ESS was lower in the donepezil arm than in the placebo arm (8.9±4.4 vs 15.7±4.1, p<0.05). Effect size for ESS was high (d 1.61). Other endpoints were not different among study arms. Randomization order didn’t affect the results. No AEs were reported. Conclusion Donepezil improved subjective sleepiness in individuals with RES. To our knowledge, this is the first study to report the effects of a cholinergic intervention in patients with RES. Effect size was high for self-reported sleepiness, which may impact on quality of life and risk of disability in people with RES. Agents acting on the cholinergic system are potential targets for treating RES. Support Acknowledgements Brazilian National Council for Scientific and Technological Development (CNPq) This study is supported by AFIP (Associacao Fundo Incentivo a Pesquisa).

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The Gamification of Meditation: A Randomized-Controlled Study of a Prescribed Mobile Mindfulness Meditation Application in Reducing College Students’ Depression

Simulation & Gaming ◽

10.1177/1046878119851821 ◽

2019 ◽

Vol 50 (4) ◽

pp. 419-435 ◽

Cited By ~ 4

Author(s):

Matthew T. Fish ◽

Amelia D. Saul

Keyword(s):

College Students ◽

Symptom Severity ◽

Repeated Measures ◽

Mindfulness Meditation ◽

Controlled Study ◽

Control Group ◽

Depression Symptom ◽

Health Providers ◽

Severity Scores ◽

Experimental Group

Objective. Roughly 35% of college students report depression as a significant concern, which unaddressed, can lead to an increased likelihood to quit school and develop comorbid conditions. Traditional depression interventions are useful; however, they are often expensive, stigmatizing, tedious, and time-intensive. We examined a prescribed mindfulness meditation regimen, which incorporates gamification principles, in reducing symptoms of depression compared to a control group. Materials and methods. We recruited and randomly assigned 72 college students to an experimental group (n = 33) or a control group (n = 39). The prescription for experimfiental group participants was ten 10-minute mobile mindfulness meditation sessions over a 14-day period; control group participants continued with business as usual. The Patient Health Questionnaire (PHQ-9) was used to test our hypothesis. Results. Repeated-measures ANOVA demonstrated a significant interaction of group by time for depression scores, supporting the hypothesis that experimental group participants would significantly decrease their depression symptom severity compared to control group participants post-intervention. Within-subjects contrasts and between-group analyses showed a significant decrease in depression symptom severity scores. Conclusion. Prescribed use of a gamified mindfulness meditation application significantly decreased depression symptom severity as measured by the PHQ-9. College students and mental health providers should consider these fun, inexpensive, and non-stigmatizing applications as a feasible intervention for college students to improve symptoms associated with depression.

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