Ganaxolone Treatment in Children With Fragile X Syndrome

A Controlled, Double-blind, Crossover Trial of Ganaxolone in Children With Fragile X Syndrome

This Phase 2 proof-of-concept study is a double-blind, randomized, placebo-controlled, crossover study to investigate ganaxolone treatment in children with fragile x syndrome (FXS). The objective of the study is to assess the safety, tolerability and efficacy of ganaxolone in the treatment of anxiety and attention in subjects with FXS.

Study Overview

• Status: Completed
• Conditions: Fragile x Syndrome
• Intervention / Treatment: Drug: Ganaxolone; Drug: Placebo

Detailed Description

This is a single center study conducted at University of California Davis (UCD) MIND Institute. Children with FXS between the ages of 6-17 years, inclusive will be randomized at a 1:1 ratio to receive ganaxolone or placebo treatment for 6 weeks, discontinue treatment and washout for 2 weeks, and then cross over to the opposite treatment for another 6 weeks.

• Study Type: Interventional
• Enrollment (Actual): 59
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Edegem, Belgium, 2650
    • Antwerp University Hospital
• United States
  • California
    • Sacramento, California, United States, 95817
      • M.I.N.D. Institute at University of California at Davis Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• molecular documentation of FMR1 full mutation
• ages 6-17 yrs, inclusive
• sexually active subjects are required to use a medically acceptable form of birth control

Exclusion Criteria:

• non-English or Spanish speaking subjects
• concomitant systemic steroid, vigabatrin, felbamate and ketoconazole
• changes in medications within last 2 months
• clinically unstable medical disease, progressive CNS disease/disorder
• history of recurrent status epilepticus
• unwilling to withhold grapefruit or grapefruit juice for the duration of the study
• actively suicidal

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ganaxolone then Placebo; Participants first received ganaxolone. They were first titrated up to the 12 milligram per kilogram (mg/kg) three times daily (tid) during a 2-week titration phase, then maintained on that dose for an additional 4 weeks. After a washout period of 2 weeks, participants received placebo for a duration of 6 weeks (from week 8 to 14).	Drug: Ganaxolone; oral suspension, given in 3 divided doses; Other Names: GNX; GNX OS; Drug: Placebo; oral suspension, given in 3 divided doses; Other Names: PBO
Experimental: Placebo then Ganaxolone; Participants first received placebo. They were first titrated up to the 12 mg/kg tid during a 2-week titration phase, then maintained on that dose for an additional 4 weeks. After a washout period of 2 weeks, participants received ganaxolone for a duration of 6 weeks (from week 8 to 14).	Drug: Ganaxolone; oral suspension, given in 3 divided doses; Other Names: GNX; GNX OS; Drug: Placebo; oral suspension, given in 3 divided doses; Other Names: PBO

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Global Impression-Improvement (CGI-I) Scale	The CGI-I scale is a clinician-rated 7-point scale used to assess how much the participant's illness had improved or worsened relative to a Baseline state at the beginning of the intervention. It was rated as: 1. "very much improved"; 2. "much improved"; 3. "minimally improved"; 4. "no change"; 5. "minimally worse"; 6. "much worse"; 7. "very much worse". Higher scores indicated worse condition.	Week 14 (End of Treatment)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pediatric Anxiety Rating Scale (PARS) Total Score	Pediatric Anxiety Rating Scale (PARS) is a clinician administered measure of anxiety in children and adolescents. The PARS is comprised of a 50-item symptom checklist used to determine the presence or absence of specific anxiety symptoms during the prior week and 7 severity/impairment items, each scored from 0 to 5. The score on the 7 items allows the clinician to rate symptom severity and associated impairment on a range from 0 to 35, with higher scores reflecting greater symptom severity and associated impairment.	Week 14 (End of Treatment)
Visual Analogue Scale (VAS)	A semi-structured VAS design was employed, providing two of the three behaviors to be assessed as anxiety and attention, chosen by caregiver(s) of one additional behavior from a bank of five. This bank included sociability, attention, aggression, language, and hyperactivity/impulsivity. Parents mark on a visual line measuring 10 centimeters (cm) with "worst behavior" at 0 cm and "best behavior" at 10 cm. For each behavior the caregiver is instructed to mark their impression of behavior at Baseline visit and again at each visit. The calculated distance in cm between the baseline and each visit marks thereby demonstrates whether each behavior improved, worsened, or stayed the same during the study, and by how much. Shown here is the least square mean distance and its corresponding standard error in cm from the "worst behavior" side, at baseline. Smaller the value, worser the behavior.	Week 14 (End of Treatment)
Anxiety, Depression, and Mood Scale (ADAMS)	The ADAMS is a 28-item behavior-based informant instrument rated by the parent(s), legal authorized guardian(s), or consistent caregiver(s). The scale is composed of 5 factors, which addresses Manic/Hyperactive Behavior, Depressed Mood, Social Avoidance, General Anxiety, and Obsessive/Compulsive Behavior. Items are scored on a 0-3 Likert scale that combines frequency and severity ratings (where 0=behavior has not occurred or is not a problem, 3=behavior occurs a lot or is a severe problem). Each subscale score is calculated separately; the scale range for Manic/Hyperactive Behavior is 0-15; for Depressed Mood, 0-21; for Social Avoidance, 0-21; for General Anxiety, 0-21; for Obsessive Behavior, 0-9. There is an overlapped item between Manic/Hypertension Behavior and General Anxiety; hence, the subscale ranges appear to reflect scores for 29 items instead of 28 items.	Week 14 (End of Treatment)
Aberrant Behavior Checklist (ABC)	The ABC is a 58-item parent rated from 0 (not at all a problem) to 3 (the problem is severe in degree with 6 subscales: Irritability (includes agitation, aggression, and self-injury, 15 items) with range of scores from 0-45; Social Withdrawal/Lethargy (16 items) with range of scores from 0-48; Stereotypy (7 items) with range of scores from 0-21; Hyperactivity (16 items) with range of scores from 0-48; Inappropriate Speech (4 items) with range of scores from 0-12 and Social avoidance (4 items) with range of scores from 0-12. Higher scores indicated greater severity. Social Withdrawal and Lethargy are reporting the same scale and Social Avoidance is a subscale of Social Withdrawal; hence, the subscale ranges appear to reflect scores for 62 items instead of 58 items.	Week 14 (End of Treatment)
Swanson, Nolan, and Pelham-IV Questionnaire (SNAP-IV)	The SNAP-IV is a revision of the Swanson, Nolan, and Pelham (SNAP) Questionnaire. The SNAP-IV: ADHD Inattention Subscale (items 1-9) scores the intensity of each item during the last seven days on a 0 to 3 scale (0=not at all, 1=just a little, 2=pretty much, 3=very much). Possible scores ranged from 0-27; higher scores indicated a greater intensity. The SNAP-IV ADHD Hyperactivity/Impulsivity Subscale (items 10-18) scores the intensity of each item in the last seven days on a 0 to 3 scale (0=not at all, 1=just a little, 2=pretty much, 3=very much). Possible scores ranged from 0-27; higher scores indicated a greater intensity. SNAP-IV ADHD Combined Scale score (inattention + hyperactivity/impulsivity) ranged from 0-54. A low score of 0 indicates less inattention + hyperactivity/impulsivity. A high score of 54 indicates more inattention + hyperactivity.	Week 14 (End of Treatment)

Other Outcome Measures

Outcome Measure	Time Frame
KiTAP- Test of Attentional Performance for Children	Baseline, Weeks 6, 8, 14
Prepulse Inhibition (PPI)	Baseline, Weeks 6, 8, 14
Social Gaze (eye tracking)	Baseline, Weeks 6, 8, 14
Event-related brain potentials (ERP)	Baseline, Weeks 6, 8, 14

Collaborators and Investigators

• Sponsor: Marinus Pharmaceuticals
• Collaborators: University of California, Davis; U.S. Army Medical Research and Development Command
• Investigators: Principal Investigator: Randi J Hagerman, MD, M.I.N.D. Institute at University of California at Davis Medical Center; Principal Investigator: Berten Ceulemans, M.D.; Ph. D., University Hospital, Antwerp

Publications and helpful links

General Publications

• Ligsay A, Van Dijck A, Nguyen DV, Lozano R, Chen Y, Bickel ES, Hessl D, Schneider A, Angkustsiri K, Tassone F, Ceulemans B, Kooy RF, Hagerman RJ. A randomized double-blind, placebo-controlled trial of ganaxolone in children and adolescents with fragile X syndrome. J Neurodev Disord. 2017 Aug 2;9(1):26. doi: 10.1186/s11689-017-9207-8.

Study record dates

Study Major Dates

• Study Start: November 1, 2012
• Primary Completion (Actual): October 16, 2015
• Study Completion (Actual): November 1, 2016

Study Registration Dates

• First Submitted: November 7, 2012
• First Submitted That Met QC Criteria: November 8, 2012
• First Posted (Estimate): November 12, 2012

Study Record Updates

• Last Update Posted (Actual): April 10, 2023
• Last Update Submitted That Met QC Criteria: March 15, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: pediatric; anxiety; ganaxolone; attention; fragile x syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Disease; Congenital Abnormalities; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Mental Retardation, X-Linked; Intellectual Disability; Heredodegenerative Disorders, Nervous System; Chromosome Disorders; Sex Chromosome Disorders; Syndrome; Fragile X Syndrome; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; GABA Modulators; GABA Agents; Neurosteroids; Ganaxolone
• Other Study ID Numbers: 1042-0800