Arbaclofen in fragile X syndrome: results of phase 3 trials

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

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

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 fragile X syndrome: results of phase 3 trials

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

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

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.

randomised clinical trial Arbaclofen placarbil in gastro oesophageal reflux disease insights into study design for transient lower sphincter relaxation inhibitors

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

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

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