A randomized double-blind, placebo-controlled trial of ganaxolone in children and adolescents with fragile X syndrome

Andrew Ligsay, Anke Van Dijck, Danh V. Nguyen, Reymundo Lozano, Yanjun Chen, Erika S. Bickel, David R Hessl, Andrea Schneider, Kathleen Angkustsiri, Flora Tassone, Berten Ceulemans, R. Frank Kooy, Randi J Hagerman

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Background: Gamma-aminobutyric acid (GABA) system deficits are integral to the pathophysiologic development of fragile X syndrome (FXS). Ganaxolone, a GABAA receptor positive allosteric modulator, is hypothesized to improve symptoms such as anxiety, hyperactivity, and attention deficits in children with FXS. Methods: This study was a randomized, double-blind, placebo-controlled, crossover trial of ganaxolone in children with FXS, aged 6-17 years. Results: Sixty-one participants were assessed for eligibility, and 59 were randomized to the study. Fifty-five participants completed at least the first arm and were included in the intention-to-treat analysis; 51 participants completed both treatment arms. There were no statistically significant improvements observed on the primary outcome measure (Clinical Global Impression-Improvement), the key secondary outcome measure (Pediatric Anxiety Rating Scale-R), or any other secondary outcome measures in the overall study population. However, post-hoc analyses revealed positive trends in areas of anxiety, attention, and hyperactivity in participants with higher baseline anxiety and low full-scale IQ scores. No serious adverse events (AEs) occurred, although there was a significant increase in the frequency and severity of AEs related to ganaxolone compared to placebo. Conclusions: While ganaxolone was found to be safe, there were no significant improvements in the outcome measures in the overall study population. However, ganaxolone in subgroups of children with FXS, including those with higher anxiety or lower cognitive abilities, might have beneficial effects. Trial registration: ClinicalTrials.gov, NCT01725152

Original languageEnglish (US)
Article number26
JournalJournal of Neurodevelopmental Disorders
Volume9
Issue number1
DOIs
StatePublished - Aug 2 2017

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Fragile X Syndrome
Anxiety
Placebos
Outcome Assessment (Health Care)
Intention to Treat Analysis
Aptitude
GABA-A Receptors
Cross-Over Studies
gamma-Aminobutyric Acid
Population
ganaxolone
Pediatrics

Keywords

  • Adolescents
  • Children
  • Clinical trial
  • Fragile X syndrome
  • Ganaxolone

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cognitive Neuroscience

Cite this

A randomized double-blind, placebo-controlled trial of ganaxolone in children and adolescents with fragile X syndrome. / Ligsay, Andrew; Van Dijck, Anke; Nguyen, Danh V.; Lozano, Reymundo; Chen, Yanjun; Bickel, Erika S.; Hessl, David R; Schneider, Andrea; Angkustsiri, Kathleen; Tassone, Flora; Ceulemans, Berten; Kooy, R. Frank; Hagerman, Randi J.

In: Journal of Neurodevelopmental Disorders, Vol. 9, No. 1, 26, 02.08.2017.

Research output: Contribution to journalArticle

Ligsay, Andrew ; Van Dijck, Anke ; Nguyen, Danh V. ; Lozano, Reymundo ; Chen, Yanjun ; Bickel, Erika S. ; Hessl, David R ; Schneider, Andrea ; Angkustsiri, Kathleen ; Tassone, Flora ; Ceulemans, Berten ; Kooy, R. Frank ; Hagerman, Randi J. / A randomized double-blind, placebo-controlled trial of ganaxolone in children and adolescents with fragile X syndrome. In: Journal of Neurodevelopmental Disorders. 2017 ; Vol. 9, No. 1.
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abstract = "Background: Gamma-aminobutyric acid (GABA) system deficits are integral to the pathophysiologic development of fragile X syndrome (FXS). Ganaxolone, a GABAA receptor positive allosteric modulator, is hypothesized to improve symptoms such as anxiety, hyperactivity, and attention deficits in children with FXS. Methods: This study was a randomized, double-blind, placebo-controlled, crossover trial of ganaxolone in children with FXS, aged 6-17 years. Results: Sixty-one participants were assessed for eligibility, and 59 were randomized to the study. Fifty-five participants completed at least the first arm and were included in the intention-to-treat analysis; 51 participants completed both treatment arms. There were no statistically significant improvements observed on the primary outcome measure (Clinical Global Impression-Improvement), the key secondary outcome measure (Pediatric Anxiety Rating Scale-R), or any other secondary outcome measures in the overall study population. However, post-hoc analyses revealed positive trends in areas of anxiety, attention, and hyperactivity in participants with higher baseline anxiety and low full-scale IQ scores. No serious adverse events (AEs) occurred, although there was a significant increase in the frequency and severity of AEs related to ganaxolone compared to placebo. Conclusions: While ganaxolone was found to be safe, there were no significant improvements in the outcome measures in the overall study population. However, ganaxolone in subgroups of children with FXS, including those with higher anxiety or lower cognitive abilities, might have beneficial effects. Trial registration: ClinicalTrials.gov, NCT01725152",
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AU - Ligsay, Andrew

AU - Van Dijck, Anke

AU - Nguyen, Danh V.

AU - Lozano, Reymundo

AU - Chen, Yanjun

AU - Bickel, Erika S.

AU - Hessl, David R

AU - Schneider, Andrea

AU - Angkustsiri, Kathleen

AU - Tassone, Flora

AU - Ceulemans, Berten

AU - Kooy, R. Frank

AU - Hagerman, Randi J

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N2 - Background: Gamma-aminobutyric acid (GABA) system deficits are integral to the pathophysiologic development of fragile X syndrome (FXS). Ganaxolone, a GABAA receptor positive allosteric modulator, is hypothesized to improve symptoms such as anxiety, hyperactivity, and attention deficits in children with FXS. Methods: This study was a randomized, double-blind, placebo-controlled, crossover trial of ganaxolone in children with FXS, aged 6-17 years. Results: Sixty-one participants were assessed for eligibility, and 59 were randomized to the study. Fifty-five participants completed at least the first arm and were included in the intention-to-treat analysis; 51 participants completed both treatment arms. There were no statistically significant improvements observed on the primary outcome measure (Clinical Global Impression-Improvement), the key secondary outcome measure (Pediatric Anxiety Rating Scale-R), or any other secondary outcome measures in the overall study population. However, post-hoc analyses revealed positive trends in areas of anxiety, attention, and hyperactivity in participants with higher baseline anxiety and low full-scale IQ scores. No serious adverse events (AEs) occurred, although there was a significant increase in the frequency and severity of AEs related to ganaxolone compared to placebo. Conclusions: While ganaxolone was found to be safe, there were no significant improvements in the outcome measures in the overall study population. However, ganaxolone in subgroups of children with FXS, including those with higher anxiety or lower cognitive abilities, might have beneficial effects. Trial registration: ClinicalTrials.gov, NCT01725152

AB - Background: Gamma-aminobutyric acid (GABA) system deficits are integral to the pathophysiologic development of fragile X syndrome (FXS). Ganaxolone, a GABAA receptor positive allosteric modulator, is hypothesized to improve symptoms such as anxiety, hyperactivity, and attention deficits in children with FXS. Methods: This study was a randomized, double-blind, placebo-controlled, crossover trial of ganaxolone in children with FXS, aged 6-17 years. Results: Sixty-one participants were assessed for eligibility, and 59 were randomized to the study. Fifty-five participants completed at least the first arm and were included in the intention-to-treat analysis; 51 participants completed both treatment arms. There were no statistically significant improvements observed on the primary outcome measure (Clinical Global Impression-Improvement), the key secondary outcome measure (Pediatric Anxiety Rating Scale-R), or any other secondary outcome measures in the overall study population. However, post-hoc analyses revealed positive trends in areas of anxiety, attention, and hyperactivity in participants with higher baseline anxiety and low full-scale IQ scores. No serious adverse events (AEs) occurred, although there was a significant increase in the frequency and severity of AEs related to ganaxolone compared to placebo. Conclusions: While ganaxolone was found to be safe, there were no significant improvements in the outcome measures in the overall study population. However, ganaxolone in subgroups of children with FXS, including those with higher anxiety or lower cognitive abilities, might have beneficial effects. Trial registration: ClinicalTrials.gov, NCT01725152

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