PMID- 28616094 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20191120 IS - 1866-1947 (Print) IS - 1866-1955 (Electronic) IS - 1866-1947 (Linking) VI - 9 DP - 2017 TI - Arbaclofen in fragile X syndrome: results of phase 3 trials. PG - 3 LID - 10.1186/s11689-016-9181-6 [doi] LID - 3 AB - 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 < 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. FAU - Berry-Kravis, Elizabeth AU - Berry-Kravis E AD - Departments of Pediatrics, Neurological Sciences, Biochemistry, Rush University Medical Center, 1725 West Harrison, Suite 718, Chicago, IL 60612 USA. ISNI: 0000 0001 0705 3621. GRID: grid.240684.c FAU - Hagerman, Randi AU - Hagerman R AD - MIND Institute and Department of Pediatrics, University of California Davis Medical Center, 2825 50th Street, Sacramento, CA 95817 USA. ISNI: 0000 0000 9752 8549. GRID: grid.413079.8 FAU - Visootsak, Jeannie AU - Visootsak J AD - Department of Human Genetics, Emory University, 2165 N. Decatur Road, Decatur, GA 30033 USA. ISNI: 0000 0001 0941 6502. GRID: grid.189967.8 FAU - Budimirovic, Dejan AU - Budimirovic D AD - Departments of Psychiatry &Behavioral Sciences, Kennedy Krieger Institute, the Johns Hopkins Medical Institutions, 716 N. Broadway, Room 246, Baltimore, MD 21205 USA. ISNI: 0000 0001 2171 9311. GRID: grid.21107.35 FAU - Kaufmann, Walter E AU - Kaufmann WE AD - Department of Neurology, Boston Children's Hospital, Boston, MA 02115 and Greenwood Genetic Center, Greenwood, SC 29646, USA. ISNI: 0000 0000 8571 0933. GRID: grid.418307.9 FAU - Cherubini, Maryann AU - Cherubini M AD - Seaside Therapeutics Inc, 124 Washington Street, Suite 101, Foxboro, MA 02035, USA. FAU - Zarevics, Peter AU - Zarevics P AD - Seaside Therapeutics Inc, 124 Washington Street, Suite 101, Foxboro, MA 02035, USA. FAU - Walton-Bowen, Karen AU - Walton-Bowen K AD - Simons Foundation Autism Research Initiative, 160 Fifth Avenue, 7th Floor, New York, NY 10010, USA. GRID: grid.430264.7 FAU - Wang, Paul AU - Wang P AD - Autism Speaks, 1 East 33rd Street, 4th Floor, New York, NY 10016, USA. ISNI: 0000 0004 4663 7867. GRID: grid.427598.5 FAU - Bear, Mark F AU - Bear MF AD - The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, 43 Vassar Street, 46-3301, Cambridge, MA 02139, USA. ISNI: 0000 0001 2341 2786. GRID: grid.116068.8 FAU - Carpenter, Randall L AU - Carpenter RL AD - The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, 43 Vassar Street, 46-3301, Cambridge, MA 02139, USA. ISNI: 0000 0001 2341 2786. GRID: grid.116068.8 AD - Rett Syndrome Research Trust, 67 Under Cliff Rd, Trumbull, CT 06611, USA. LA - eng PT - Journal Article DEP - 20170612 PL - England TA - J Neurodev Disord JT - Journal of neurodevelopmental disorders JID - 101483832 PMC - PMC5467054 OTO - NOTNLM OT - Arbaclofen OT - FMR1 OT - Fragile X syndrome OT - GABA agonist OT - Neurodevelopmental disorder OT - Targeted treatment EDAT- 2017/06/16 06:00 MHDA- 2017/06/16 06:01 PMCR- 2017/06/12 CRDT- 2017/06/16 06:00 PHST- 2016/05/10 00:00 [received] PHST- 2016/12/07 00:00 [accepted] PHST- 2017/06/16 06:00 [entrez] PHST- 2017/06/16 06:00 [pubmed] PHST- 2017/06/16 06:01 [medline] PHST- 2017/06/12 00:00 [pmc-release] AID - 9181 [pii] AID - 10.1186/s11689-016-9181-6 [doi] PST - epublish SO - J Neurodev Disord. 2017 Jun 12;9:3. doi: 10.1186/s11689-016-9181-6. eCollection 2017.