Ganaxolone Treatment in Children With Fragile X Syndrome

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.

• Ganaxolone (Drug): oral suspension, given in 3 divided doses
• Placebo (Drug): oral suspension, given in 3 divided doses

Primary outcomes

• Clinical Global Impression-Improvement (CGI-I) Scale [Week 14 (End of Treatment)]: 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.

Secondary outcomes

• Pediatric Anxiety Rating Scale (PARS) Total Score [Week 14 (End of Treatment)]: 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.
• Visual Analogue Scale (VAS) [Week 14 (End of Treatment)]: 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.
• Anxiety, Depression, and Mood Scale (ADAMS) [Week 14 (End of Treatment)]: 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.
• Aberrant Behavior Checklist (ABC) [Week 14 (End of Treatment)]: 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.
• Swanson, Nolan, and Pelham-IV Questionnaire (SNAP-IV) [Week 14 (End of Treatment)]: 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.

Sex: All, ages: 6 Years to 17 Years

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

Participant flow

Outcome results

• Clinical Global Impression-Improvement (CGI-I) Scale (Primary), Least squares mean, Scores on a scale: Ganaxolone 3.4 +/- 0.13; Placebo 3.5 +/- 0.13 (p 0.4475)
• Pediatric Anxiety Rating Scale (PARS) Total Score (Secondary), Least squares mean, Scores on a scale: Ganaxolone 8.3 +/- 0.54; Placebo 9.2 +/- 0.54
• Visual Analogue Scale (VAS) (Secondary), Least squares mean, Centimeters (cm): Ganaxolone 5.6 +/- 0.27; Placebo 5.0 +/- 0.26
• Anxiety, Depression, and Mood Scale (ADAMS) (Secondary), Least squares mean, Scores on a scale: Ganaxolone 7.4 +/- 0.42; Placebo 7.8 +/- 0.40
• Aberrant Behavior Checklist (ABC) (Secondary), Least squares mean, Scores on a scale: Ganaxolone 15.7 +/- 0.87; Placebo 16.1 +/- 0.86
• Swanson, Nolan, and Pelham-IV Questionnaire (SNAP-IV) (Secondary), Least squares mean, Scores on a scale: Ganaxolone 15.5 +/- 0.66; Placebo 14.6 +/- 0.62

Adverse events

Time frame: Up to 14 Weeks

Other adverse events by term

45 more terms not shown.

• Results publication: 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. PMID 28764646