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Peter Zarevics - One of the best experts on this subject based on the ideXlab platform.

  • Arbaclofen in fragile X syndrome: results of phase 3 trials
    Journal of Neurodevelopmental Disorders, 2017
    Co-Authors: Elizabeth Berry-kravis, Randi Hagerman, Jeannie Visootsak, Dejan B. Budimirovic, Walter E. Kaufmann, Maryann Cherubini, Peter Zarevics, Karen Walton-bowen, Paul Wang, Mark F. Bear
    Abstract:

    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. 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. 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 

  • Arbaclofen in fragile X syndrome: results of phase 3 trials
    Journal of Neurodevelopmental Disorders, 2017
    Co-Authors: Elizabeth Berry-kravis, Randi Hagerman, Jeannie Visootsak, Dejan B. Budimirovic, Walter E. Kaufmann, Maryann Cherubini, Peter Zarevics, Karen Walton-bowen, Paul Wang, Mark F. Bear
    Abstract:

    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-C_FX). Secondary outcomes included other ABC-C_FX 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-C_FX Irritability subscale ( p  = 0.03) and Parenting Stress Index (PSI, p  = 0.03) and trends toward benefit on the ABC-C_FX Social Avoidance and Hyperactivity subscales (both p  

  • Arbaclofen in fragile x syndrome results of phase 3 trials
    Journal of Neurodevelopmental Disorders, 2017
    Co-Authors: Elizabeth Berrykravis, Randi Hagerman, Jeannie Visootsak, Dejan B. Budimirovic, Walter E. Kaufmann, Maryann Cherubini, Peter Zarevics, Paul Wang, Karen Waltonbowen, Mark F. Bear
    Abstract:

    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. 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. 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). 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.

  • Arbaclofen in Children and Adolescents with Autism Spectrum Disorder: A Randomized, Controlled, Phase 2 Trial
    Neuropsychopharmacology, 2017
    Co-Authors: Jeremy Veenstra-vanderweele, Maryann Cherubini, Peter Zarevics, Karen Walton-bowen, Mark F. Bear, Edwin H Cook, Bryan H King, Paul P Wang, Randall L Carpenter
    Abstract:

    Several lines of emerging data point to an imbalance between neuronal excitation and inhibition in at least a subgroup of individuals with autism spectrum disorder (ASD), including in those with fragile X syndrome (FXS), one of the most common genetic syndromes within ASD. In animal models of FXS and of ASD, GABA-B agonists have improved both brain and behavioral phenotypes, including social behavior. A phase 2 randomized, placebo-controlled, crossover trial found that the GABA-B agonist Arbaclofen improved social avoidance symptoms in FXS. A pilot open-label trial of Arbaclofen suggested similar benefits in ASD. We therefore evaluated Arbaclofen in a randomized, placebo-controlled, phase 2 study of 150 participants, aged 5–21 years, with ASD. No difference from placebo was detected on the primary outcome measure, the parent-rated Aberrant Behavior Checklist Social Withdrawal/Lethargy subscale. However, a specified secondary analysis found improvement on the clinician-rated Clinical Global Impression of Severity. An exploratory post hoc analysis of participants with a consistent rater across the trial revealed greater improvement in the Vineland Adaptive Behavior Scales II socialization domain in participants receiving Arbaclofen. Affect lability (11%) and sedation (9%) were the most common adverse events. In this exploratory study, secondary analyses suggest that Arbaclofen may have the potential to improve symptoms in some children with ASD, but further study will be needed to replicate and extend these initial findings.

  • Arbaclofen in Children and Adolescents with Autism Spectrum Disorder: A Randomized, Controlled, Phase 2 Trial
    Neuropsychopharmacology, 2016
    Co-Authors: Jeremy Veenstra-vanderweele, Maryann Cherubini, Peter Zarevics, Karen Walton-bowen, Mark F. Bear, Edwin H Cook, Bryan H King, Paul P Wang, Randall L Carpenter
    Abstract:

    Arbaclofen in Children and Adolescents with Autism Spectrum Disorder: A Randomized, Controlled, Phase 2 Trial

Maryann Cherubini - One of the best experts on this subject based on the ideXlab platform.

  • Arbaclofen in fragile X syndrome: results of phase 3 trials
    Journal of Neurodevelopmental Disorders, 2017
    Co-Authors: Elizabeth Berry-kravis, Randi Hagerman, Jeannie Visootsak, Dejan B. Budimirovic, Walter E. Kaufmann, Maryann Cherubini, Peter Zarevics, Karen Walton-bowen, Paul Wang, Mark F. Bear
    Abstract:

    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. 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. 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 

  • Arbaclofen in fragile X syndrome: results of phase 3 trials
    Journal of Neurodevelopmental Disorders, 2017
    Co-Authors: Elizabeth Berry-kravis, Randi Hagerman, Jeannie Visootsak, Dejan B. Budimirovic, Walter E. Kaufmann, Maryann Cherubini, Peter Zarevics, Karen Walton-bowen, Paul Wang, Mark F. Bear
    Abstract:

    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-C_FX). Secondary outcomes included other ABC-C_FX 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-C_FX Irritability subscale ( p  = 0.03) and Parenting Stress Index (PSI, p  = 0.03) and trends toward benefit on the ABC-C_FX Social Avoidance and Hyperactivity subscales (both p  

  • Arbaclofen in fragile x syndrome results of phase 3 trials
    Journal of Neurodevelopmental Disorders, 2017
    Co-Authors: Elizabeth Berrykravis, Randi Hagerman, Jeannie Visootsak, Dejan B. Budimirovic, Walter E. Kaufmann, Maryann Cherubini, Peter Zarevics, Paul Wang, Karen Waltonbowen, Mark F. Bear
    Abstract:

    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. 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. 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). 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.

  • Arbaclofen in Children and Adolescents with Autism Spectrum Disorder: A Randomized, Controlled, Phase 2 Trial
    Neuropsychopharmacology, 2017
    Co-Authors: Jeremy Veenstra-vanderweele, Maryann Cherubini, Peter Zarevics, Karen Walton-bowen, Mark F. Bear, Edwin H Cook, Bryan H King, Paul P Wang, Randall L Carpenter
    Abstract:

    Several lines of emerging data point to an imbalance between neuronal excitation and inhibition in at least a subgroup of individuals with autism spectrum disorder (ASD), including in those with fragile X syndrome (FXS), one of the most common genetic syndromes within ASD. In animal models of FXS and of ASD, GABA-B agonists have improved both brain and behavioral phenotypes, including social behavior. A phase 2 randomized, placebo-controlled, crossover trial found that the GABA-B agonist Arbaclofen improved social avoidance symptoms in FXS. A pilot open-label trial of Arbaclofen suggested similar benefits in ASD. We therefore evaluated Arbaclofen in a randomized, placebo-controlled, phase 2 study of 150 participants, aged 5–21 years, with ASD. No difference from placebo was detected on the primary outcome measure, the parent-rated Aberrant Behavior Checklist Social Withdrawal/Lethargy subscale. However, a specified secondary analysis found improvement on the clinician-rated Clinical Global Impression of Severity. An exploratory post hoc analysis of participants with a consistent rater across the trial revealed greater improvement in the Vineland Adaptive Behavior Scales II socialization domain in participants receiving Arbaclofen. Affect lability (11%) and sedation (9%) were the most common adverse events. In this exploratory study, secondary analyses suggest that Arbaclofen may have the potential to improve symptoms in some children with ASD, but further study will be needed to replicate and extend these initial findings.

  • Arbaclofen in Children and Adolescents with Autism Spectrum Disorder: A Randomized, Controlled, Phase 2 Trial
    Neuropsychopharmacology, 2016
    Co-Authors: Jeremy Veenstra-vanderweele, Maryann Cherubini, Peter Zarevics, Karen Walton-bowen, Mark F. Bear, Edwin H Cook, Bryan H King, Paul P Wang, Randall L Carpenter
    Abstract:

    Arbaclofen in Children and Adolescents with Autism Spectrum Disorder: A Randomized, Controlled, Phase 2 Trial

Nimish Vakil - One of the best experts on this subject based on the ideXlab platform.

  • randomised clinical trial Arbaclofen placarbil in gastro oesophageal reflux disease insights into study design for transient lower sphincter relaxation inhibitors
    Alimentary Pharmacology & Therapeutics, 2013
    Co-Authors: Nimish Vakil, F J Huff, Kenneth C Cundy
    Abstract:

    Summary Background Arbaclofen placarbil is a pro-drug of the gamma-aminobutyric acid-B agonist R-baclofen that has been shown to reduce reflux episodes in patients with gastro-oesophageal reflux disease (GERD). Aim To evaluate the efficacy and safety of Arbaclofen placarbil vs. placebo as adjunctive therapy in subjects with troublesome GERD symptoms despite therapy with once-daily doses of a proton pump inhibitor (PPI) and to identify the characteristics of patients who were responders. Methods Patients (n = 460) with symptomatic GERD experiencing troublesome symptoms on once-daily PPI therapy were enrolled in this phase II, randomised, multicentre, double-blind, placebo-controlled, dose-ranging study. Patients were randomised to receive placebo or Arbaclofen placarbil (20 or 40 mg once daily, 20 or 30 mg twice daily) with their current PPI for 6 weeks. Patients recorded heartburn and other GERD symptoms in a daily diary and rated severity of each event. The primary endpoint was percent change from baseline in heartburn events per week. Results In the primary analysis, there was no significant difference between Arbaclofen placarbil and placebo. Post hoc analyses removing mild and very mild heartburn events resulted in greater percent reductions for all Arbaclofen placarbil doses with nominal P values <0.05 for each dose compared with placebo. There was a dose-related increase for the most common adverse events. Conclusions Arbaclofen placarbil was not superior to placebo in the primary analysis. Post hoc analyses suggest that subjects with more clinically relevant moderate or severe symptoms are more likely to respond to Arbaclofen placarbil (clinicaltrials.gov NCT00978016).

  • Randomised clinical trial: Arbaclofen placarbil in gastro‐oesophageal reflux disease – insights into study design for transient lower sphincter relaxation inhibitors
    Alimentary Pharmacology & Therapeutics, 2013
    Co-Authors: Nimish Vakil, F J Huff, Kenneth C Cundy
    Abstract:

    Summary Background Arbaclofen placarbil is a pro-drug of the gamma-aminobutyric acid-B agonist R-baclofen that has been shown to reduce reflux episodes in patients with gastro-oesophageal reflux disease (GERD). Aim To evaluate the efficacy and safety of Arbaclofen placarbil vs. placebo as adjunctive therapy in subjects with troublesome GERD symptoms despite therapy with once-daily doses of a proton pump inhibitor (PPI) and to identify the characteristics of patients who were responders. Methods Patients (n = 460) with symptomatic GERD experiencing troublesome symptoms on once-daily PPI therapy were enrolled in this phase II, randomised, multicentre, double-blind, placebo-controlled, dose-ranging study. Patients were randomised to receive placebo or Arbaclofen placarbil (20 or 40 mg once daily, 20 or 30 mg twice daily) with their current PPI for 6 weeks. Patients recorded heartburn and other GERD symptoms in a daily diary and rated severity of each event. The primary endpoint was percent change from baseline in heartburn events per week. Results In the primary analysis, there was no significant difference between Arbaclofen placarbil and placebo. Post hoc analyses removing mild and very mild heartburn events resulted in greater percent reductions for all Arbaclofen placarbil doses with nominal P values

  • Arbaclofen placarbil in gerd a randomized double blind placebo controlled study
    The American Journal of Gastroenterology, 2011
    Co-Authors: Nimish Vakil, Jacob F Huff, Amy Bian, Drew S Jones, David Stamler
    Abstract:

    OBJECTIVES:It has been shown that Arbaclofen placarbil (AP) inhibits reflux in gastroesophageal reflux disease (GERD) following single oral dosing. This study evaluated the efficacy and safety of AP over 4 weeks in subjects with symptomatic GERD.METHODS:One hundred fifty-six subjects with heartburn

Mark F. Bear - One of the best experts on this subject based on the ideXlab platform.

  • Arbaclofen in fragile X syndrome: results of phase 3 trials
    Journal of Neurodevelopmental Disorders, 2017
    Co-Authors: Elizabeth Berry-kravis, Randi Hagerman, Jeannie Visootsak, Dejan B. Budimirovic, Walter E. Kaufmann, Maryann Cherubini, Peter Zarevics, Karen Walton-bowen, Paul Wang, Mark F. Bear
    Abstract:

    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. 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. 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 

  • Arbaclofen in fragile X syndrome: results of phase 3 trials
    Journal of Neurodevelopmental Disorders, 2017
    Co-Authors: Elizabeth Berry-kravis, Randi Hagerman, Jeannie Visootsak, Dejan B. Budimirovic, Walter E. Kaufmann, Maryann Cherubini, Peter Zarevics, Karen Walton-bowen, Paul Wang, Mark F. Bear
    Abstract:

    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-C_FX). Secondary outcomes included other ABC-C_FX 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-C_FX Irritability subscale ( p  = 0.03) and Parenting Stress Index (PSI, p  = 0.03) and trends toward benefit on the ABC-C_FX Social Avoidance and Hyperactivity subscales (both p  

  • Arbaclofen in fragile x syndrome results of phase 3 trials
    Journal of Neurodevelopmental Disorders, 2017
    Co-Authors: Elizabeth Berrykravis, Randi Hagerman, Jeannie Visootsak, Dejan B. Budimirovic, Walter E. Kaufmann, Maryann Cherubini, Peter Zarevics, Paul Wang, Karen Waltonbowen, Mark F. Bear
    Abstract:

    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. 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. 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). 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.

  • Arbaclofen in Children and Adolescents with Autism Spectrum Disorder: A Randomized, Controlled, Phase 2 Trial
    Neuropsychopharmacology, 2017
    Co-Authors: Jeremy Veenstra-vanderweele, Maryann Cherubini, Peter Zarevics, Karen Walton-bowen, Mark F. Bear, Edwin H Cook, Bryan H King, Paul P Wang, Randall L Carpenter
    Abstract:

    Several lines of emerging data point to an imbalance between neuronal excitation and inhibition in at least a subgroup of individuals with autism spectrum disorder (ASD), including in those with fragile X syndrome (FXS), one of the most common genetic syndromes within ASD. In animal models of FXS and of ASD, GABA-B agonists have improved both brain and behavioral phenotypes, including social behavior. A phase 2 randomized, placebo-controlled, crossover trial found that the GABA-B agonist Arbaclofen improved social avoidance symptoms in FXS. A pilot open-label trial of Arbaclofen suggested similar benefits in ASD. We therefore evaluated Arbaclofen in a randomized, placebo-controlled, phase 2 study of 150 participants, aged 5–21 years, with ASD. No difference from placebo was detected on the primary outcome measure, the parent-rated Aberrant Behavior Checklist Social Withdrawal/Lethargy subscale. However, a specified secondary analysis found improvement on the clinician-rated Clinical Global Impression of Severity. An exploratory post hoc analysis of participants with a consistent rater across the trial revealed greater improvement in the Vineland Adaptive Behavior Scales II socialization domain in participants receiving Arbaclofen. Affect lability (11%) and sedation (9%) were the most common adverse events. In this exploratory study, secondary analyses suggest that Arbaclofen may have the potential to improve symptoms in some children with ASD, but further study will be needed to replicate and extend these initial findings.

  • Arbaclofen in Children and Adolescents with Autism Spectrum Disorder: A Randomized, Controlled, Phase 2 Trial
    Neuropsychopharmacology, 2016
    Co-Authors: Jeremy Veenstra-vanderweele, Maryann Cherubini, Peter Zarevics, Karen Walton-bowen, Mark F. Bear, Edwin H Cook, Bryan H King, Paul P Wang, Randall L Carpenter
    Abstract:

    Arbaclofen in Children and Adolescents with Autism Spectrum Disorder: A Randomized, Controlled, Phase 2 Trial

Karen Walton-bowen - One of the best experts on this subject based on the ideXlab platform.

  • Arbaclofen in fragile X syndrome: results of phase 3 trials
    Journal of Neurodevelopmental Disorders, 2017
    Co-Authors: Elizabeth Berry-kravis, Randi Hagerman, Jeannie Visootsak, Dejan B. Budimirovic, Walter E. Kaufmann, Maryann Cherubini, Peter Zarevics, Karen Walton-bowen, Paul Wang, Mark F. Bear
    Abstract:

    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. 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. 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 

  • Arbaclofen in fragile X syndrome: results of phase 3 trials
    Journal of Neurodevelopmental Disorders, 2017
    Co-Authors: Elizabeth Berry-kravis, Randi Hagerman, Jeannie Visootsak, Dejan B. Budimirovic, Walter E. Kaufmann, Maryann Cherubini, Peter Zarevics, Karen Walton-bowen, Paul Wang, Mark F. Bear
    Abstract:

    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-C_FX). Secondary outcomes included other ABC-C_FX 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-C_FX Irritability subscale ( p  = 0.03) and Parenting Stress Index (PSI, p  = 0.03) and trends toward benefit on the ABC-C_FX Social Avoidance and Hyperactivity subscales (both p  

  • Arbaclofen in Children and Adolescents with Autism Spectrum Disorder: A Randomized, Controlled, Phase 2 Trial
    Neuropsychopharmacology, 2017
    Co-Authors: Jeremy Veenstra-vanderweele, Maryann Cherubini, Peter Zarevics, Karen Walton-bowen, Mark F. Bear, Edwin H Cook, Bryan H King, Paul P Wang, Randall L Carpenter
    Abstract:

    Several lines of emerging data point to an imbalance between neuronal excitation and inhibition in at least a subgroup of individuals with autism spectrum disorder (ASD), including in those with fragile X syndrome (FXS), one of the most common genetic syndromes within ASD. In animal models of FXS and of ASD, GABA-B agonists have improved both brain and behavioral phenotypes, including social behavior. A phase 2 randomized, placebo-controlled, crossover trial found that the GABA-B agonist Arbaclofen improved social avoidance symptoms in FXS. A pilot open-label trial of Arbaclofen suggested similar benefits in ASD. We therefore evaluated Arbaclofen in a randomized, placebo-controlled, phase 2 study of 150 participants, aged 5–21 years, with ASD. No difference from placebo was detected on the primary outcome measure, the parent-rated Aberrant Behavior Checklist Social Withdrawal/Lethargy subscale. However, a specified secondary analysis found improvement on the clinician-rated Clinical Global Impression of Severity. An exploratory post hoc analysis of participants with a consistent rater across the trial revealed greater improvement in the Vineland Adaptive Behavior Scales II socialization domain in participants receiving Arbaclofen. Affect lability (11%) and sedation (9%) were the most common adverse events. In this exploratory study, secondary analyses suggest that Arbaclofen may have the potential to improve symptoms in some children with ASD, but further study will be needed to replicate and extend these initial findings.

  • Arbaclofen in Children and Adolescents with Autism Spectrum Disorder: A Randomized, Controlled, Phase 2 Trial
    Neuropsychopharmacology, 2016
    Co-Authors: Jeremy Veenstra-vanderweele, Maryann Cherubini, Peter Zarevics, Karen Walton-bowen, Mark F. Bear, Edwin H Cook, Bryan H King, Paul P Wang, Randall L Carpenter
    Abstract:

    Arbaclofen in Children and Adolescents with Autism Spectrum Disorder: A Randomized, Controlled, Phase 2 Trial

  • STX209 (Arbaclofen) for Autism Spectrum Disorders: An 8-Week Open-Label Study
    Journal of Autism and Developmental Disorders, 2014
    Co-Authors: Craig A. Erickson, Maryann Cherubini, Peter Zarevics, Jeremy M. Veenstra-vanderweele, Raun D. Melmed, James T. Mccracken, Lawrence D. Ginsberg, Linmarie Sikich, Lawrence Scahill, Karen Walton-bowen
    Abstract:

    STX209 (Arbaclofen), a selective GABA-B agonist, is hypothesized to modulate the balance of excitatory to inhibitory neurotransmission, and has shown preliminary evidence of benefit in fragile X syndrome. We evaluated its safety, tolerability, and efficacy in non-syndromic autism spectrum disorders, in an 8-week open-label trial enrolling 32 children and adolescents with either Autistic Disorder or Pervasive Developmental Disorder—Not Otherwise Specified, and a score ≥17 on the Aberrant Behavior Checklist (ABC)—Irritability subscale. STX209 was generally well-tolerated. The most common adverse events were agitation and irritability, which typically resolved without dose changes, and were often felt to represent spontaneous variation in underlying symptoms. Improvements were observed on several outcome measures in this exploratory trial, including the ABC-Irritability (the primary endpoint) and the Lethargy/Social Withdrawal subscales, the Social Responsiveness Scale, the CY-BOCS-PDD, and clinical global impression scales. Placebo-controlled study of STX209 is warranted.