Arbaclofen in fragile X syndrome: results of phase 3 trials / Elizabeth BERRY-KRAVIS in Journal of Neurodevelopmental Disorders, 9-1 (December 2017)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 9-1 (December 2017) . - p.3 Titre : Arbaclofen in fragile X syndrome: results of phase 3 trials Type de document : texte imprimé Auteurs : Elizabeth BERRY-KRAVIS, Auteur ; Randi J. HAGERMAN, Auteur ; Jeannie VISOOTSAK, Auteur ; Dejan B. BUDIMIROVIC, Auteur ; Walter E. KAUFMANN, Auteur ; Maryann CHERUBINI, Auteur ; Peter ZAREVICS, Auteur ; Karen WALTON-BOWEN, Auteur ; Ping WANG, Auteur ; Mark F. BEAR, Auteur ; Randall L. CARPENTER, Auteur Article en page(s) : p.3 Langues : Anglais (eng) Mots-clés : Arbaclofen  Fmr1  Fragile X syndrome  GABA agonist  Neurodevelopmental disorder  Targeted treatment Index. décimale : PER Périodiques Résumé : BACKGROUND: Arbaclofen improved multiple abnormal phenotypes in animal models of fragile X syndrome (FXS) and showed promising results in a phase 2 clinical study. The objective of the study is to determine safety and efficacy of arbaclofen for social avoidance in FXS. METHODS: Two phase 3 placebo-controlled trials were conducted, a flexible dose trial in subjects age 12-50 (209FX301, adolescent/adult study) and a fixed dose trial in subjects age 5-11 (209FX302, child study). The primary endpoint for both trials was the Social Avoidance subscale of the Aberrant Behavior Checklist-Community Edition, FXS-specific (ABC-CFX). Secondary outcomes included other ABC-CFX subscale scores, Clinical Global Impression-Improvement (CGI-I), Clinical Global Impression-Severity (CGI-S), and Vineland Adaptive Behavior Scales, Second Edition (Vineland-II) Socialization domain score. RESULTS: A total 119 of 125 randomized subjects completed the adolescent/adult study (n = 57 arbaclofen, 62 placebo) and 159/172 completed the child study (arbaclofen 5 BID n = 38; 10 BID n = 39; 10 TID n = 38; placebo n = 44). There were no serious adverse events (AEs); the most common AEs included somatic (headache, vomiting, nausea), neurobehavioral (irritability/agitation, anxiety, hyperactivity), decreased appetite, and infectious conditions, many of which were also common on placebo. In the combined studies, there were 13 discontinuations (n = 12 arbaclofen, 1 placebo) due to AEs (all neurobehavioral). The adolescent/adult study did not show benefit for arbaclofen over placebo for any measure. In the child study, the highest dose group showed benefit over placebo on the ABC-CFX Irritability subscale (p = 0.03) and Parenting Stress Index (PSI, p = 0.03) and trends toward benefit on the ABC-CFX Social Avoidance and Hyperactivity subscales (both p < 0.1) and CGI-I (p = 0.119). Effect size in the highest dose group was similar to effect sizes for FDA-approved serotonin reuptake inhibitors (SSRIs). CONCLUSIONS: Arbaclofen did not meet the primary outcome of improved social avoidance in FXS in either study. Data from secondary measures in the child study suggests younger patients may derive benefit, but additional studies with a larger cohort on higher doses would be required to confirm this finding. The reported studies illustrate the challenges but represent a significant step forward in translating targeted treatments from preclinical models to clinical trials in humans with FXS. En ligne : http://dx.doi.org/10.1186/s11689-016-9181-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=349 [article] Arbaclofen in fragile X syndrome: results of phase 3 trials [texte imprimé] / Elizabeth BERRY-KRAVIS, Auteur ; Randi J. HAGERMAN, Auteur ; Jeannie VISOOTSAK, Auteur ; Dejan B. BUDIMIROVIC, Auteur ; Walter E. KAUFMANN, Auteur ; Maryann CHERUBINI, Auteur ; Peter ZAREVICS, Auteur ; Karen WALTON-BOWEN, Auteur ; Ping WANG, Auteur ; Mark F. BEAR, Auteur ; Randall L. CARPENTER, Auteur . - p.3. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 9-1 (December 2017) . - p.3 Mots-clés : Arbaclofen  Fmr1  Fragile X syndrome  GABA agonist  Neurodevelopmental disorder  Targeted treatment Index. décimale : PER Périodiques Résumé : BACKGROUND: Arbaclofen improved multiple abnormal phenotypes in animal models of fragile X syndrome (FXS) and showed promising results in a phase 2 clinical study. The objective of the study is to determine safety and efficacy of arbaclofen for social avoidance in FXS. METHODS: Two phase 3 placebo-controlled trials were conducted, a flexible dose trial in subjects age 12-50 (209FX301, adolescent/adult study) and a fixed dose trial in subjects age 5-11 (209FX302, child study). The primary endpoint for both trials was the Social Avoidance subscale of the Aberrant Behavior Checklist-Community Edition, FXS-specific (ABC-CFX). Secondary outcomes included other ABC-CFX subscale scores, Clinical Global Impression-Improvement (CGI-I), Clinical Global Impression-Severity (CGI-S), and Vineland Adaptive Behavior Scales, Second Edition (Vineland-II) Socialization domain score. RESULTS: A total 119 of 125 randomized subjects completed the adolescent/adult study (n = 57 arbaclofen, 62 placebo) and 159/172 completed the child study (arbaclofen 5 BID n = 38; 10 BID n = 39; 10 TID n = 38; placebo n = 44). There were no serious adverse events (AEs); the most common AEs included somatic (headache, vomiting, nausea), neurobehavioral (irritability/agitation, anxiety, hyperactivity), decreased appetite, and infectious conditions, many of which were also common on placebo. In the combined studies, there were 13 discontinuations (n = 12 arbaclofen, 1 placebo) due to AEs (all neurobehavioral). The adolescent/adult study did not show benefit for arbaclofen over placebo for any measure. In the child study, the highest dose group showed benefit over placebo on the ABC-CFX Irritability subscale (p = 0.03) and Parenting Stress Index (PSI, p = 0.03) and trends toward benefit on the ABC-CFX Social Avoidance and Hyperactivity subscales (both p < 0.1) and CGI-I (p = 0.119). Effect size in the highest dose group was similar to effect sizes for FDA-approved serotonin reuptake inhibitors (SSRIs). CONCLUSIONS: Arbaclofen did not meet the primary outcome of improved social avoidance in FXS in either study. Data from secondary measures in the child study suggests younger patients may derive benefit, but additional studies with a larger cohort on higher doses would be required to confirm this finding. The reported studies illustrate the challenges but represent a significant step forward in translating targeted treatments from preclinical models to clinical trials in humans with FXS. En ligne : http://dx.doi.org/10.1186/s11689-016-9181-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=349

A randomized, double-blind, placebo-controlled phase II trial to explore the effects of a GABA(A)-α5 NAM (basmisanil) on intellectual disability associated with Down syndrome / Celia GOELDNER in Journal of Neurodevelopmental Disorders, 14 (2022)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 14 (2022) Titre : A randomized, double-blind, placebo-controlled phase II trial to explore the effects of a GABA(A)-α5 NAM (basmisanil) on intellectual disability associated with Down syndrome Type de document : texte imprimé Auteurs : Celia GOELDNER, Auteur ; Priya S. KISHNANI, Auteur ; Brian G. SKOTKO, Auteur ; Julian Lirio CASERO, Auteur ; Joerg F. HIPP, Auteur ; Michael DERKS, Auteur ; Maria-Clemencia HERNANDEZ, Auteur ; Omar KHWAJA, Auteur ; Sian LENNON-CHRIMES, Auteur ; Jana NOELDEKE, Auteur ; Sabine PELLICER, Auteur ; Lisa SQUASSANTE, Auteur ; Jeannie VISOOTSAK, Auteur ; Christoph WANDEL, Auteur ; Paulo FONTOURA, Auteur ; Xavier Liogier D'ARDHUY, Auteur ; CLEMATIS STUDY GROUP, Auteur Langues : Anglais (eng) Mots-clés : Adolescent  Child  Child, Preschool  Down Syndrome/complications/drug therapy  Humans  Intellectual Disability/complications/drug therapy  Morpholines  Oxazoles  Pyridines  Quality of Life  Treatment Outcome  Young Adult  gamma-Aminobutyric Acid/therapeutic use  Adaptive behavior  Cognition  Down syndrome  Eeg  GABAA-α5  Khwaja, X Liogier d’Ardhuy, J Noeldeke, S Pellicer, L Squassante, C Wandel were  employees of F.Hoffmann-La Roche AG Switzerland  M Derks and S Lennon-Chrimes  were employees of Roche Products Ltd. UK  J Visootsak was an employee of Roche  New York. All employees (former and current) may be eligible for stock and stock  options. P S Kishnani has no disclosures for Down syndrome-related research. J  Lirio Casero has no disclosures. B G Skotko occasionally consults on the topic of  Down syndrome through the Gerson Lehrman Group. He receives remuneration from  Down syndrome non-profit organizations for speaking engagements and associated  travel expenses. Dr. Skotko receives annual royalties from Woodbine House, Inc.,  for the publication of his book, Fasten Your Seatbelt: A Crash Course on Down  Syndrome for Brothers and Sisters. Within the past 2 years, he has also received  research funding from AC Immune and LuMind Research Down Syndrome Foundation to  conduct clinical trials for people with Down syndrome. Dr. Skotko is occasionally  asked to serve as an expert witness for legal cases where Down syndrome is  discussed. Dr. Skotko serves in a non-paid capacity on the Honorary Board of  Directors for the Massachusetts Down Syndrome Congress and the Professional  Advisory Committee for the National Center for Prenatal and Postnatal Down  Syndrome Resources. Dr. Skotko has a sister with Down syndrome. Index. décimale : PER Périodiques Résumé : BACKGROUND: There are currently no pharmacological therapies to address the intellectual disability associated with Down syndrome. Excitatory/inhibitory imbalance has been hypothesized to contribute to impairments in cognitive functioning in Down syndrome. Negative modulation of the GABA(A)-α5 receptor is proposed as a mechanism to attenuate GABAergic function and restore the excitatory/inhibitory balance. METHODS: Basmisanil, a selective GABA(A)-α5 negative allosteric modulator, was evaluated at 120 mg or 240 mg BID (80 or 160 mg for 12-13 years) in a 6-month, randomized, double-blind, placebo-controlled phase II trial (Clematis) for efficacy and safety in adolescents and young adults with Down syndrome. The primary endpoint was based on a composite analysis of working memory (Repeatable Battery for the Assessment of Neuropsychological Scale [RBANS]) and independent functioning and adaptive behavior (Vineland Adaptive Behavior Scales [VABS-II] or the Clinical Global Impression-Improvement [CGI-I]). Secondary measures included the Behavior Rating Inventory of Executive Functioning-Preschool (BRIEF-P), Clinical Evaluation of Language Fundamentals (CELF-4), and Pediatric Quality of Life Inventory (Peds-QL). EEG was conducted for safety monitoring and quantitatively analyzed in adolescents. RESULTS: Basmisanil was safe and well-tolerated; the frequency and nature of adverse events were similar in basmisanil and placebo arms. EEG revealed treatment-related changes in spectral power (increase in low ~ 4-Hz and decrease in high ~ 20-Hz frequencies) providing evidence of functional target engagement. All treatment arms had a similar proportion of participants showing above-threshold improvement on the primary composite endpoint, evaluating concomitant responses in cognition and independent functioning (29% in placebo, 20% in low dose, and 25% in high dose). Further analysis of the individual measures contributing to the primary endpoint revealed no difference between placebo and basmisanil-treated groups in either adolescents or adults. There were also no differences across the secondary endpoints assessing changes in executive function, language, or quality of life. CONCLUSIONS: Basmisanil did not meet the primary efficacy objective of concomitant improvement on cognition and adaptive functioning after 6 months of treatment, despite evidence for target engagement. This study provides key learnings for future clinical trials in Down syndrome. TRIAL REGISTRATION: The study was registered on December 31, 2013, at clinicaltrials.gov as NCT02024789. En ligne : https://dx.doi.org/10.1186/s11689-022-09418-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574 [article] A randomized, double-blind, placebo-controlled phase II trial to explore the effects of a GABA(A)-α5 NAM (basmisanil) on intellectual disability associated with Down syndrome [texte imprimé] / Celia GOELDNER, Auteur ; Priya S. KISHNANI, Auteur ; Brian G. SKOTKO, Auteur ; Julian Lirio CASERO, Auteur ; Joerg F. HIPP, Auteur ; Michael DERKS, Auteur ; Maria-Clemencia HERNANDEZ, Auteur ; Omar KHWAJA, Auteur ; Sian LENNON-CHRIMES, Auteur ; Jana NOELDEKE, Auteur ; Sabine PELLICER, Auteur ; Lisa SQUASSANTE, Auteur ; Jeannie VISOOTSAK, Auteur ; Christoph WANDEL, Auteur ; Paulo FONTOURA, Auteur ; Xavier Liogier D'ARDHUY, Auteur ; CLEMATIS STUDY GROUP, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 14 (2022) Mots-clés : Adolescent  Child  Child, Preschool  Down Syndrome/complications/drug therapy  Humans  Intellectual Disability/complications/drug therapy  Morpholines  Oxazoles  Pyridines  Quality of Life  Treatment Outcome  Young Adult  gamma-Aminobutyric Acid/therapeutic use  Adaptive behavior  Cognition  Down syndrome  Eeg  GABAA-α5  Khwaja, X Liogier d’Ardhuy, J Noeldeke, S Pellicer, L Squassante, C Wandel were  employees of F.Hoffmann-La Roche AG Switzerland  M Derks and S Lennon-Chrimes  were employees of Roche Products Ltd. UK  J Visootsak was an employee of Roche  New York. All employees (former and current) may be eligible for stock and stock  options. P S Kishnani has no disclosures for Down syndrome-related research. J  Lirio Casero has no disclosures. B G Skotko occasionally consults on the topic of  Down syndrome through the Gerson Lehrman Group. He receives remuneration from  Down syndrome non-profit organizations for speaking engagements and associated  travel expenses. Dr. Skotko receives annual royalties from Woodbine House, Inc.,  for the publication of his book, Fasten Your Seatbelt: A Crash Course on Down  Syndrome for Brothers and Sisters. Within the past 2 years, he has also received  research funding from AC Immune and LuMind Research Down Syndrome Foundation to  conduct clinical trials for people with Down syndrome. Dr. Skotko is occasionally  asked to serve as an expert witness for legal cases where Down syndrome is  discussed. Dr. Skotko serves in a non-paid capacity on the Honorary Board of  Directors for the Massachusetts Down Syndrome Congress and the Professional  Advisory Committee for the National Center for Prenatal and Postnatal Down  Syndrome Resources. Dr. Skotko has a sister with Down syndrome. Index. décimale : PER Périodiques Résumé : BACKGROUND: There are currently no pharmacological therapies to address the intellectual disability associated with Down syndrome. Excitatory/inhibitory imbalance has been hypothesized to contribute to impairments in cognitive functioning in Down syndrome. Negative modulation of the GABA(A)-α5 receptor is proposed as a mechanism to attenuate GABAergic function and restore the excitatory/inhibitory balance. METHODS: Basmisanil, a selective GABA(A)-α5 negative allosteric modulator, was evaluated at 120 mg or 240 mg BID (80 or 160 mg for 12-13 years) in a 6-month, randomized, double-blind, placebo-controlled phase II trial (Clematis) for efficacy and safety in adolescents and young adults with Down syndrome. The primary endpoint was based on a composite analysis of working memory (Repeatable Battery for the Assessment of Neuropsychological Scale [RBANS]) and independent functioning and adaptive behavior (Vineland Adaptive Behavior Scales [VABS-II] or the Clinical Global Impression-Improvement [CGI-I]). Secondary measures included the Behavior Rating Inventory of Executive Functioning-Preschool (BRIEF-P), Clinical Evaluation of Language Fundamentals (CELF-4), and Pediatric Quality of Life Inventory (Peds-QL). EEG was conducted for safety monitoring and quantitatively analyzed in adolescents. RESULTS: Basmisanil was safe and well-tolerated; the frequency and nature of adverse events were similar in basmisanil and placebo arms. EEG revealed treatment-related changes in spectral power (increase in low ~ 4-Hz and decrease in high ~ 20-Hz frequencies) providing evidence of functional target engagement. All treatment arms had a similar proportion of participants showing above-threshold improvement on the primary composite endpoint, evaluating concomitant responses in cognition and independent functioning (29% in placebo, 20% in low dose, and 25% in high dose). Further analysis of the individual measures contributing to the primary endpoint revealed no difference between placebo and basmisanil-treated groups in either adolescents or adults. There were also no differences across the secondary endpoints assessing changes in executive function, language, or quality of life. CONCLUSIONS: Basmisanil did not meet the primary efficacy objective of concomitant improvement on cognition and adaptive functioning after 6 months of treatment, despite evidence for target engagement. This study provides key learnings for future clinical trials in Down syndrome. TRIAL REGISTRATION: The study was registered on December 31, 2013, at clinicaltrials.gov as NCT02024789. En ligne : https://dx.doi.org/10.1186/s11689-022-09418-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574

Sex chromosome aneuploidy / Jeannie VISOOTSAK

Public ISBD in Autism and Other Neurodevelopmental Disorders / Robin L. HANSEN Titre : Sex chromosome aneuploidy Type de document : texte imprimé Auteurs : Jeannie VISOOTSAK, Auteur ; Nicole TARTAGLIA, Auteur Année de publication : 2013 Importance : p.195-225 Langues : Anglais (eng) Index. décimale : TRO-F TRO-F - Autres Troubles Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=190 in Autism and Other Neurodevelopmental Disorders / Robin L. HANSEN Sex chromosome aneuploidy [texte imprimé] / Jeannie VISOOTSAK, Auteur ; Nicole TARTAGLIA, Auteur . - 2013 . - p.195-225. Langues : Anglais (eng) Index. décimale : TRO-F TRO-F - Autres Troubles Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=190

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